Dynamics of Cell Differentiation
Lead Research Organisation:
University of Dundee
Department Name: Mathematics & Computer Science
Abstract
It is well-known that identical living cells within complex multi-celluar organisms (e.g. humans) can respond to environmental signals and perform different, but co-ordinated roles. One of the most striking examples of this is in embryo development. This process is due to ?cell differentiation? and until recently, it was thought this behaviour was only found in complex, multi-cellular organisms. However, recently it has been discovered that simple single-celled organisms such as bacteria, also display cell differentiation and so to some extent can behave as multi-cellular collectives . One of the most striking examples of cell differentiation in bacteria occurs in the formation of biofilms. A biofilm contains billions of individual cells encased in a self-produced polymer glue. Despite each bacterial cell being genetically identical, the community soon differentiates into sub-populations, each carrying out a different role. Just how this complex multi-cellular decision making process occurs is far from understood. Almost all bacteria that occur in the natural environment live in these closely-knit biofilms and they are important to all aspects of our lives e.g. human health, the effective treatment of sewage and even daily dental care: plaque is a bacterial biofilm.
The overall aim of this work is to better understand how differences in the way genes within individual bacterial cells respond to environmental signals leads to the segregation of these cells into sub-populations, each of which behaves in an entirely different, but apparently co-ordinated, manner. In this project I will focus on the well-studied bacterium Bacillus subtilis, which is used to produce enzymes for cleaning products (e.g. biological washing powder) and has growing potential as an alternative and environmentally friendly pesticide. Biofilms are so complex and cover such a wide range of scales (it would take 1000 cells laid end-to-end to cross a pin head but biofilms can be centimetres or even metres across) that it is necessary to take an inter-disciplinary ?systems? approach. I intend to use a combination of powerful modern mathematical modelling techniques supported by state-of-the-art molecular biology experimental procedures and will work closely with biofilm expert Dr Nicola-Stanley Wall, University of Dundee. Very recently, I appear to have uncovered an entirely new mathematical theory that may explain cell differentiation. It is this exciting discovery that motivates the work of this proposal.
The overall aim of this work is to better understand how differences in the way genes within individual bacterial cells respond to environmental signals leads to the segregation of these cells into sub-populations, each of which behaves in an entirely different, but apparently co-ordinated, manner. In this project I will focus on the well-studied bacterium Bacillus subtilis, which is used to produce enzymes for cleaning products (e.g. biological washing powder) and has growing potential as an alternative and environmentally friendly pesticide. Biofilms are so complex and cover such a wide range of scales (it would take 1000 cells laid end-to-end to cross a pin head but biofilms can be centimetres or even metres across) that it is necessary to take an inter-disciplinary ?systems? approach. I intend to use a combination of powerful modern mathematical modelling techniques supported by state-of-the-art molecular biology experimental procedures and will work closely with biofilm expert Dr Nicola-Stanley Wall, University of Dundee. Very recently, I appear to have uncovered an entirely new mathematical theory that may explain cell differentiation. It is this exciting discovery that motivates the work of this proposal.
Technical Summary
It has been long understood that isogenic (genetically identical) cells in complex living organisms can perform different, but co-ordinated roles. This is dependent on cell differentiation and until very recently, it was thought that this behaviour was restricted to multi-cellular organisms. However, through recent technical advances a fascinating discovery has been made: simple, single-celled organisms such as bacteria, also display cell differentiation and so to some extent can behave as multi-cellular collectives . It has been postulated that this within-speices variation may be essential for survival in a changing environment. Cell differentiation in bacteria is now attracting intense interest as it is clear that understanding this process may be central to future developments in e.g. medicine, biocontrol and biotechnology. The overall aim of this proposal is to use multi-scale mathematical modelling combined with a complementary experimental programme to better understand how perturbations to gene transcription pathways within isogenic bacterial cell populations can lead to changes in the macro-scale organisation and function of that population.
One of the most striking examples of bacterial cell differentiation is within a biofilm - a multicellular sessile community of bacteria encased within a self-produced polymeric matrix. It is thought that over 90% of bacteria in the natural environment exist in this form.
In this project we will focus on biofilm formation in Bacillus subtilis as it is a tractable model system and also important in its own right. Because of the complexity of growth dynamics and the range of scales involved, it is necessary to take a systems approach and I intend to use a combination of deterministic and stochastic modelling techniques. This modelling work will be complemented by an experimental programme conducted in the laboratory of Dr Nicola-Stanley Wall, University of Dundee with whom I have formed a recent and exciting collaboration. In particular, I appear to have uncovered a new mathematical theory, which may explain how bimodality (cell differentiation) within a population could occur without bistability of the underlying gene network dynamics. It is this exciting discovery that motivates the work of this proposal.
Specific objective are: (i) to expand and underpin our understanding of the interplay between key components of the gene transcription network and in particular our new mechanism of ?bimodality without bistability? and (ii) to scale-up this information to construct predicative models of sub-population interactions at the biofilm-scale.
One of the most striking examples of bacterial cell differentiation is within a biofilm - a multicellular sessile community of bacteria encased within a self-produced polymeric matrix. It is thought that over 90% of bacteria in the natural environment exist in this form.
In this project we will focus on biofilm formation in Bacillus subtilis as it is a tractable model system and also important in its own right. Because of the complexity of growth dynamics and the range of scales involved, it is necessary to take a systems approach and I intend to use a combination of deterministic and stochastic modelling techniques. This modelling work will be complemented by an experimental programme conducted in the laboratory of Dr Nicola-Stanley Wall, University of Dundee with whom I have formed a recent and exciting collaboration. In particular, I appear to have uncovered a new mathematical theory, which may explain how bimodality (cell differentiation) within a population could occur without bistability of the underlying gene network dynamics. It is this exciting discovery that motivates the work of this proposal.
Specific objective are: (i) to expand and underpin our understanding of the interplay between key components of the gene transcription network and in particular our new mechanism of ?bimodality without bistability? and (ii) to scale-up this information to construct predicative models of sub-population interactions at the biofilm-scale.
