Isalan, Mark - Imperial College London - Department of Life Sciences, Biology, Ecology and Environmental Biology, Microbiology, Zoology

个人简介

Mark Isalan carried out a Ph.D. in engineering zinc fingers to bind new DNA sequences at the MRC LMB, in the University of Cambridge UK,1996-2000. This work was supervised by Prof. Sir Aaron Klug, OM, FRS, and continued postdoctorally from 2000-2002 at Gendaq Ltd, UK (now owned by Sangamo Biosciences, Richmond CA). The work ultimately contributed to the CompoZr zinc finger nucleases now available commercially from Sigma Aldrich. From 2002-2006 Dr. Isalan was awarded a Wellcome Trust International Research Fellowship to carry out research on engineering artificial gene networks in Prof. Luis Serrano's group at the EMBL Heidelberg, Germany. From 2006-2013 he was a group leader at the EMBL-CRG Systems Biology Unit in Barcelona, specialising in synthetic gene network engineering. He moved to Imperial College London in 2013 and continues to work in protein and gene network engineering, aiming to design biological systems that behave predictably and robustly.

研究领域

Our group is interested in engineering synthetic gene networks to control gene expression in cells and to construct self-organising patterns, analogous to those used by organisms in morphogenesis and development. By building artificial gene networks, we hope to find the 'design principles' underlying why certain networks form particular structures or functions. A number techniques are used to achieve these aims: (i) Protein engineering - to apply combinatorial and design approaches for constructing novel gene network components, such as our method for building customised zinc fingers to bind any desired DNA sequence (Nature Biotechnology 19, 656-60, 2001). We are continuing this work with by developing a zinc finger gene therapy for Huntington's disease (PNAS 109 (45), E3136–E3145, 2012). Our latest work shows long-term repression of mutant Huntingtin for 6 months in mice after a single injection (Molecular Neurodegeneration 2016 11:64). (ii) Computer modelling and network analysis - to test gene network hypotheses. Recently, we published two essays comparing gene networks to self-referential arguments in ancient Greek philosophy (Nature 458:969, 2009; Bioessays 31(10):1110-5, 2009). These essays explain intuitively how a fish might make stripe patterns, and why static network arrow diagrams are dangerous. We remain very interested in emergent phenomena such as Turing patterns. Looking at transcription networks in E. coli, we asked the question, "What happens when you add lots of new connections to an existing large gene network?". By shuffling E. coli transcription networks with promoter-ORF fusions we found that networks are very tolerant to rewiring (Nature 452:840-5, 2008). We have continued this work with a large-scale transcriptomics analysis of ~85 rewired networks that reveals how perturbations propagate across networks (Nature Communications 6, 2015). (iii) Synthetic Gene Network construction - to obtain desired patterns or behaviours of gene expression. For example, we built a activator-repressor gene network to read synthetic morphogen gradients (PLoS Biology 3(3), e64, 2005). This work culminated in a comprehensive analysis of all the ways to make a stripe in a morphogen gradient, developing a new network engineering methodology to explore a whole network design space (Nature Communications 5, 2014). We have a number of projects, ranging from purely basic science to those with medical and biotechnological applications. Ultimately, we aim to engineer synthetic gene networks to carry out programmed functions in a robust and predictable manner, in both bacterial and mammalian cells.

近期论文

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Toczek M, Kutryb-Zajac B, Zukowska P, Slominska E, Isalan M, Mielcarek M, Smolenski Ret al., Changes in Cardiac Nucleotide Metabolism in Huntington’s Disease, Nucleosides, Nucleotides and Nucleic Acids, ISSN: 1525-7770 Agustin-Pavon C, Mielcarek M, Garriga-Canut M, Isalan Met al., 2016, Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice, MOLECULAR NEURODEGENERATION, Vol: 11, ISSN: 1750-1326 Ciechonska M, Grob A, Isalan M, 2016, From noise to synthetic nucleoli: can synthetic biology achieve new insights?, INTEGRATIVE BIOLOGY, Vol: 8, Pages: 383-393, ISSN: 1757-9694 Toczek M, Zielonka D, Zukowska P, Marcinkowski JT, Slominska E, Isalan M, Smolenski RT, Mielcarek Met al., 2016, An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy, BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, Vol: 1862, Pages: 2147-2157, ISSN: 0925-4439 Baumstark R, Haenzelmann S, Tsuru S, Schaerli Y, Francesconi M, Mancuso FM, Castelo R, Isalan Met al., 2015, The propagation of perturbations in rewired bacterial gene networks, NATURE COMMUNICATIONS, Vol: 6, ISSN: 2041-1723 Diambra L, Raj Senthivel V, Barcena Menendez D, Isalan Met al., 2015, Cooperativity To Increase Turing Pattern Space for Synthetic Biology, ACS SYNTHETIC BIOLOGY, Vol: 4, Pages: 177-186, ISSN: 2161-5063 Menendez DB, Senthivel VR, Isalan M, 2015, Sender-receiver systems and applying information theory for quantitative synthetic biology, CURRENT OPINION IN BIOTECHNOLOGY, Vol: 31, Pages: 101-107, ISSN: 0958-1669 Mielcarek M, Isalan M, 2015, A shared mechanism of muscle wasting in cancer and Huntington's disease., Clin Transl Med, Vol: 4 Agustin-Pavon C, Isalan M, 2014, Synthetic biology and therapeutic strategies for the degenerating brain Synthetic biology approaches can transform classical cell and gene therapies, to provide new cures for neurodegenerative diseases, BIOESSAYS, Vol: 36, Pages: 979-990, ISSN: 0265-9247 Herrman F, Isalan M, 2014, High-throughput ‘On Chip’ Protein and Nucleic Acid Transfection (2nd Edition), eLS, Publisher: John Wiley and Sons, Inc., ISBN: 9780470015902 Marucci L, Pedone E, Di Vicino U, Sanuy-Escribano B, Isalan M, Pia Cosma Met al., 2014, beta-Catenin Fluctuates in Mouse ESCs and Is Essential for Nanog-Mediated Reprogramming of Somatic Cells to Pluripotency, CELL REPORTS, Vol: 8, Pages: 1686-1696, ISSN: 2211-1247 Schaerli Y, Gili M, Isalan M, 2014, A split intein T7 RNA polymerase for transcriptional AND-logic, NUCLEIC ACIDS RESEARCH, Vol: 42, Pages: 12322-12328, ISSN: 0305-1048 Schaerli Y, Munteanu A, Gili M, Cotterell J, Sharpe J, Isalan Met al., 2014, A unified design space of synthetic stripe-forming networks, NATURE COMMUNICATIONS, Vol: 5, ISSN: 2041-1723 Carvalho A, Barcena Menendez D, Raj Senthivel V, Zimmermann T, Diambra L, Isalan Met al., 2013, Genetically encoded sender-receiver system in 3D mammalian cell culture, ACS Synthetic Biology, Vol: 3, Pages: 264-272, ISSN: 2161-5063 Isalan M, 2013, Zinc Fingers, Encyclopedia of Biological Chemistry (Second Edition), Editors: Lennarz, Lane, Publisher: Elsevier Sanders PGT, Cotterell J, Sharpe J, Isalan Met al., 2013, Transfecting RNA quadruplexes results in few transcriptome perturbations, RNA BIOLOGY, Vol: 10, Pages: 205-210, ISSN: 1547-6286 Schaerli Y, Isalan M, 2013, Building synthetic gene circuits from combinatorial libraries: screening and selection strategies, MOLECULAR BIOSYSTEMS, Vol: 9, Pages: 1559-1567, ISSN: 1742-206X Garriga-Canut M, Agustin-Pavon C, Herrmann F, Sanchez A, Dierssen M, Fillat C, Isalan Met al., 2012, Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: E3136-E3145, ISSN: 0027-8424 Isalan M, 2012, Zinc-finger nucleases: how to play two good hands, NATURE METHODS, Vol: 9, Pages: 32-34, ISSN: 1548-7091 Isalan M, 2012, SYSTEMS BIOLOGY A cell in a computer, NATURE, Vol: 488, Pages: 40-41, ISSN: 0028-0836