Mads Kaern

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Mads Kaern
Cross-appointed Associate Professor, Department of Cellular and Molecular Medicine, Faculty of Medicine, Department of Physics in the Faculty of Science

Work: (613) 562-5800 ext. 8691
email: mkaern@uottawa.ca

Picture of Dr. Mads Kaern

Biography

We investigate how genes and biochemical process control living cells. We examine the ways in which the “wiring” of gene regulatory networks defines which genes are expressed and when, and how cellular individuality contributes to uncertainty in drug responses and drug resistance. Our research distinguishes itself through the use of sophisticated mathematical models and computer simulations to explain complex phenomena and guide the construction of synthetic DNA to mimic or control natural gene networks. Trainees in our lab include graduate students from the Faculties of Medicine and Science (Physics), and undergraduate students participating with the uOttawa team in the international genetically engineered machine (iGEM) competition.

The Kaern lab accepts students from graduate programs in Physics and Cellular and Molecular Medicine.

A microscopic image of yeast cells

Variability in gene expression within a population of genetically identical yeast cells.

Research Program

Our lab investigates the function and dynamics of gene regulatory networks using a “systems science” approach that combines advanced genetic engineering, single-cell and time-lapse measurements, and computational modelling and simulation. We apply this combination of synthetic, quantitative and systems approaches in research projects focusing on mechanisms of non-genetic drug resistance, variability in cellular drug responses, the mapping of genetic networks and signalling pathways, and the properties and dynamics of transcriptional regulatory network motifs. We are also engaged in research collaborations, including network inference, the modelling of cancer-killing viruses and the modelling of adult hippocampal neurogenesis.

The development of drug resistance is a major health challenge. We have been able to demonstrate theoretically that drug resistance may arise from the way that all living cells decode genetic information. We are currently seeking to demonstrate this phenomenon in the lab. This work has revealed a more complex picture in which the networks that control the expression of drug resistance genes play a central role by enabling bet-hedging and long-term non-genetic inheritance.

Patients with the same illness often respond very differently to the same treatment. This extends even to genetically identical cells treated with DNA damaging agents and cancer drugs. We have yet to pinpoint why this variability in drug responses arises, but suspect it comes from how cells integrate information from multiple pathways conveying information about DNA damage, cell cycle progression and cellular stress.

Most cells respond to stimulation and stress by altering the genes they express. To understand how this works requires understanding how different biomolecules and genes interact with one another. To facilitate the mapping of these networks and pathways, we have developed and tested experimental and computational methods that examine thousands of simultaneous interactions.

To understand the often very complicated systems that control gene expression, we investigate the network motifs that represent the fundamental building blocks of larger networks. This line of research has already revealed new fundamental insights into cellular signalling processing and enables large-scale genetic network engineering and improves the mathematical models needed to study larger, more complex networks.

Trainees joining the Kaern lab, including undergraduate students participating in the uOttawa iGEM program, have the opportunity to gain valuable expertise in molecular biology methods, advanced genetic engineering, microscopy, flow cytometry, mathematical modelling and data analysis.

Selected Publications

Bouchard-Cannon P, Mendoza-Viveros L, Yuen A, Kærn M, Cheng HY. The circadian molecular clock regulates adult hippocampal neurogenesis by controlling the timing of cell-cycle entry and exit. Cell Rep. 2013 Nov 27;5(4):961-73. doi:10.1016/j.celrep.2013.10.037. Epub 2013 Nov 21.

Phenix H, Perkins T, Kærn M. Identifiability and inference of pathway motifs by epistasis analysis. Chaos. 2013 Jun;23(2):025103. doi: 10.1063/1.4807483.

Le Bœuf F, Batenchuk C, Vähä-Koskela M, Breton S, Roy D, Lemay C, Cox J, Abdelbary H, Falls T, Waghray G, Atkins H, Stojdl D, Diallo JS, Kærn M, Bell JC. Model-based rational design of an oncolytic virus with improved therapeutic potential. Nat Commun. 2013;4:1974. doi: 10.1038/ncomms2974.

Charlebois DA, Abdennur N, Kaern M. Gene expression noise facilitates adaptation and drug resistance independently of mutation. Phys Rev Lett. 2011 Nov 18;107(21):218101. Epub 2011 Nov 14.

Phenix H, Morin K, Batenchuk C, Parker J, Abedi V, Yang L, Tepliakova L, Perkins TJ, Kærn M. Quantitative epistasis analysis and pathway inference from genetic interaction data. PLoS Comput Biol. 2011 May;7(5):e1002048. doi:10.1371/journal.pcbi.1002048. Epub 2011 May 12.

Batenchuk C, St-Pierre S, Tepliakova L, Adiga S, Szuto A, Kabbani N, Bell JC, Baetz K, Kærn M. Chromosomal position effects are linked to sir2-mediated variation in transcriptional burst size. Biophys J. 2011 May 18;100(10):L56-8. doi: 10.1016/j.bpj.2011.04.021.

Batenchuk C, Tepliakova L, Kaern M. Identification of response-modulated genetic interactions by sensitivity-based epistatic analysis. BMC Genomics. 2010 Sep 10;11:493. doi: 10.1186/1471-2164-11-493.

Zhuravel D, Fraser D, St-Pierre S, Tepliakova L, Pang WL, Hasty J, Kærn M. Phenotypic impact of regulatory noise in cellular stress-response pathways. Syst Synth Biol. 2010 Jun;4(2):105-16. doi: 10.1007/s11693-010-9055-2. Epub 2010 Apr 22.

Song C, Phenix H, Abedi V, Scott M, Ingalls BP, Kaern M, Perkins TJ. Estimating the stochastic bifurcation structure of cellular networks. PLoS Comput Biol. 2010 Mar 5;6(3):e1000699. doi: 10.1371/journal.pcbi.1000699. Erratum in: PLoS Comput Biol. 2010;6(3). doi:10.1371/annotation/9a35fa58-f81c-41b4-9fa9-c1aeedbf0fff.

Fraser D, Kaern M. A chance at survival: gene expression noise and phenotypic diversification strategies. Mol Microbiol. 2009 Mar;71(6):1333-40. doi:10.1111/j.1365-2958.2009.06605.x. Epub 2009 Feb 10. Review.

Kaern M, Elston TC, Blake WJ, Collins JJ. Stochasticity in gene expression: from theories to phenotypes. Nat Rev Genet. 2005 Jun;6(6):451-64. Review.

Kobayashi H, Kaern M, Araki M, Chung K, Gardner TS, Cantor CR, Collins JJ. Programmable cells: interfacing natural and engineered gene networks. Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8414-9. Epub 2004 May 24.

Blake WJ, Kaern M, Cantor CR, Collins JJ. Noise in eukaryotic gene expression. Nature. 2003 Apr 10;422(6932):633-7.

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