The Molecular Nose

Lead Research Organisation: University of Glasgow
Department Name: School of Life Sciences

Abstract

THE MOLECULAR NOSEMammalian cells use more genes to regulate biological processes than to carry them out. These include all fundamental processes such as cell growth, differentiation, survival, metabolism and the ability to sense and produce the correct complement of biomolecules to communicate with the environment. Complexity is further enhanced by the organization of biological processes as networks. Understanding the behaviour and responses of such complex networks will be crucial to solve eminent questions in biology. To address this need we will build a multiplexed sensor platform that can assess and quantify dynamic changes in the functional state of biochemical networks in mammalian cells, and use these data to reconstruct cell network interactions and their dynamic behaviour on a systems wide level. The concept underpinning this platform is fundamentally different from existing methods used in the biological sciences to assess cell function, and similar to the Electronic Nose , where an array of sensors is first trained with individual stimuli to establish a library of response patterns which subsequently are used to deconvolute complex inputs. The Molecular Nose will monitor the outputs of several hundred network components simultaneously in cell populations or single cells using artificial transcriptional reporters, and design a software framework and algorithms for their functional analysis. The Molecular Nose will be built in three versions. One will be constructed using molecular biology tools, and will permit to use a large array (up to 1000) of sensors. However, it requires the cell being lysed for the measurement as the detector is outside of the cell. This version will be particularly useful for training the system and establishing a large library of response patterns. The second version will be built by integrating both individual sensors and their corresponding detectors onto bar-coded nanoparticles which will be introduced into cells and read using surface enhanced resonance Raman scattering spectroscopy. This setup will use a smaller number of sensors (up to 30), but can be used to monitor responses in living cells in real time. In parallel we will develop methods for the controlled introduction of these particle libraries into cells. The third version is the stable integration of a plasmid based sensor library into the embryonic mouse stem cells with the aim to generate a transgenic sensor mouse. The stem cells also can be used for organotypic cultures and in vitro differentiation systems.The Molecular Nose will enable the systematic testing and rational interpretation of the behaviour of cellular networks. The technique is generic with a wide range of applications in both single cells and cell populations, including eminent biological problems such as the analysis of drug effects and prediction of side effects; stem cell differentiation with a view to eventually control differentiation; cell fate specification in order to support tissue engineering; genetic and biochemical networks for the production of desired proteins and metabolites by synthetically engineered pathways; and the investigation of adaptive network responses and evolution. Currently, we are lacking efficient experimental tools to analyse these complex interactions.

Publications

10 25 50

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Calderhead B. (2009) Accelerating Bayesian inference over nonlinear differential equations with Gaussian processes in Advances in Neural Information Processing Systems 21 - Proceedings of the 2008 Conference

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Donaldson R (2010) Modelling and Analysis of Biochemical Signalling Pathway Cross-talk in Electronic Proceedings in Theoretical Computer Science

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Donaldson R (2012) Modular modelling of signalling pathways and their cross-talk in Theoretical Computer Science

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Girolami M. (2009) Reversible Jump MCMC for Non-Negative matrix factorization with application to Raman spectral decomposition in Proceedings of SPIE - The International Society for Optical Engineering

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Graham D (2009) Functionalized nanoparticles for bioanalysis by SERRS. in Biochemical Society transactions

Related Projects

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EP/E032745/1 01/10/2007 10/01/2011 £4,852,537
EP/E032745/2 Transfer EP/E032745/1 10/01/2011 08/04/2012 £1,450,608
 
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Amount £681,191 (GBP)
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Sector Public
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Description Research Grant
Amount £249,035 (GBP)
Funding ID B/G006997/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
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Description Sultanate of Oman
Amount £135,500 (GBP)
Organisation Oman - Ministry of Higher Education 
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Description Technology Programme
Amount £898,862 (GBP)
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Description UCB Celltech
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Title Fluidics apparatus and fluipics substrate 
Description A fluidics apparatus is disclosed for manipulation of at least one fluid sample, typically in the form of a droplet. The apparatus has a substrate surface with a sample manipulation zone for location of the fluid sample. A transducer arrangement such as an interdigitated electrode structure on a piezoelectric body provides surface acoustic waves at the substrate surface for manipulation of the fluid sample. The substrate surface has an arrangement of surface acoustic wave scattering elements forming a phononic crystal structure for affecting the transmission, distribution and/or behaviour of surface acoustic waves at the substrate surface. Also disclosed is a method for lysing a cell. In this method, the cell is comprised in a fluid sample contacting a substrate surface, the method comprising providing surface acoustic waves at the substrate surface, such that the cell lyses. 
IP Reference WO2011023949 A2 
Protection Patent granted
Year Protection Granted 2010
Licensed No
Impact Led to a number of additional findings and patents. Now being commercialised.