Research interests: Systems and Synthetic Biology; protein and genome engineering; zinc fingers
Our group is interested in engineering synthetic gene networks to control gene expression in cells. 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 these studies 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. We recently 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 biotechnological and medical applications, including gene therapy. 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.
Links to our Partners and Funding Agencies:
European Research Council (ERC): ERC Starting Grant
The Wellcome Trust, UK: New Investigator Award - see 2013 tab
The EVOPROG consortium: http://www.evoprog.eu/
The MycoSynVac consortium: http://www.mycosynvac.eu/
The Zinc Finger Consortium: http://www.zincfingers.org/