Microfluidics for single-cell noise measurements
Lead Research Organisation:
University of Warwick
Department Name: School of Life Sciences
Abstract
The combination of microfluidics and time-lapse microscopy is a powerful one, with the potential for the generation of time-series data for single-cell measurements across a whole population of cells. This project aims to employ these tools for the development of technologies and strategies that facilitate the study of stochastic events at the single-cell level. A key focus of the work is the development of microfluidic and image analysis techniques.
Such developments within this project are being applied to study the specific example of noise within the expression of the yeast GCN4 transcriptional regulator. This is activated during amino acid starvation, through a novel post-transcriptional regulatory system. The majority of research into gene expression noise thus far has focused on transcriptional noise, so the impact of post-transcriptional regulation on noise is relatively poorly understood.
Biological systems show many apparently deterministic behaviours at the macroscopic level, but their underlying mechanisms are often stochastic in nature. Noise in gene expression generates heterogeneity across clonal cell populations, and is an important factor in many cellular processes (e.g. circadian rhythms). Even within the well-known "repressilator" synthetic gene circuit, noise had a significant impact on the circuit output. An appreciation of stochasticity in gene expression is therefore crucial for a complete understanding of biology, and will also be essential for the successful design of future synthetic biological systems.
Consequently, this project falls within the EPSRC research area of synthetic biology. Engineering of living organisms will always create populations of cells that are not all identical, and any attempt to engineer biological systems must take this heterogeneity into account. By utilising microfluidics to study both naturally occurring and engineered cell-to-cell heterogeneity in baker's yeast (Saccharomyces cerevisiae), this project aims to provide a quantitative understanding of gene expression stochasticity in this eukaryotic organism
Such developments within this project are being applied to study the specific example of noise within the expression of the yeast GCN4 transcriptional regulator. This is activated during amino acid starvation, through a novel post-transcriptional regulatory system. The majority of research into gene expression noise thus far has focused on transcriptional noise, so the impact of post-transcriptional regulation on noise is relatively poorly understood.
Biological systems show many apparently deterministic behaviours at the macroscopic level, but their underlying mechanisms are often stochastic in nature. Noise in gene expression generates heterogeneity across clonal cell populations, and is an important factor in many cellular processes (e.g. circadian rhythms). Even within the well-known "repressilator" synthetic gene circuit, noise had a significant impact on the circuit output. An appreciation of stochasticity in gene expression is therefore crucial for a complete understanding of biology, and will also be essential for the successful design of future synthetic biological systems.
Consequently, this project falls within the EPSRC research area of synthetic biology. Engineering of living organisms will always create populations of cells that are not all identical, and any attempt to engineer biological systems must take this heterogeneity into account. By utilising microfluidics to study both naturally occurring and engineered cell-to-cell heterogeneity in baker's yeast (Saccharomyces cerevisiae), this project aims to provide a quantitative understanding of gene expression stochasticity in this eukaryotic organism
Planned Impact
The emerging and dynamic field of Synthetic Biology has the potential to provide solutions to some of the key challenges faced by society, ranging across the healthcare, energy, food and environmental sectors. The UK government has recently a "Synthetic Biology Roadmap", which presents a vision and direction for Synthetic Biology in the UK. The report projects that the global Synthetic Biology market will grow from $1.6bn in 2011 to $10.8bn by 2016. It highlights that there is an urgent need for the UK to develop the interdisciplinary skills required to take advantage of the opportunities provided by Synthetic Biology.
The challenge to the academic and industrial research communities is to develop new translational approaches to ensure that these potential benefits are realised. These new approaches will range across the design and engineering of biologically based parts, devices and systems as well as the re-design of existing, natural biological systems across all scales from molecules to organisms. The techniques will encompass not only individual cells, but also self-assembled biomimetic systems, engineered microbial communities and multicellular organisms, combining multiple perspectives drawn from the engineering, life and physical sciences.
Realising these goals will require a new generation of skilled interdisciplinary scientists, and the training of these scientists is the primary goal of the SBCDT. Our programme will give the breadth of coverage to produce a "skilled, energized and well-funded UK-wide synthetic biology community", who will have "the opportunity to revolutionise major industries in bio-energy and bio-technology in the UK" (David Willetts, Minister for Universities and Science) in their future careers. This will be made possible through genuine inter-institutional collaboration in partnership with key industrial, academic and public facing institutions.
The potential impact of the SBCDT, and its potential national importance, are very therefore high, and the potential benefits to society are significant.
The challenge to the academic and industrial research communities is to develop new translational approaches to ensure that these potential benefits are realised. These new approaches will range across the design and engineering of biologically based parts, devices and systems as well as the re-design of existing, natural biological systems across all scales from molecules to organisms. The techniques will encompass not only individual cells, but also self-assembled biomimetic systems, engineered microbial communities and multicellular organisms, combining multiple perspectives drawn from the engineering, life and physical sciences.
Realising these goals will require a new generation of skilled interdisciplinary scientists, and the training of these scientists is the primary goal of the SBCDT. Our programme will give the breadth of coverage to produce a "skilled, energized and well-funded UK-wide synthetic biology community", who will have "the opportunity to revolutionise major industries in bio-energy and bio-technology in the UK" (David Willetts, Minister for Universities and Science) in their future careers. This will be made possible through genuine inter-institutional collaboration in partnership with key industrial, academic and public facing institutions.
The potential impact of the SBCDT, and its potential national importance, are very therefore high, and the potential benefits to society are significant.