SysMO: Systems Biology of Clostridium acetobutylicum - a possible answer to dwindling crude oil reserves.

The genus Clostridium are an ancient grouping of bacteria which evolved before the earth had an oxygen atmosphere. To them oxygen in the air we breathe is a poison, and they are therefore called 'anaerobes'. They are also characterised by an ability to produce a spore resting stage that enables them to survive exposure to the air. These spores are also resistant to many other physical and chemical agents. Some species cause devastating diseases. Some species cause devastating diseases, such as the superbug Clostridium difficile. On the other hand, most clostridia are entirely benign, and their ability to produce a wide range of diverse chemicals from plant material is being pursued by industry as an alternative to generating these chemicals from crude oil. Principle amongst these is C. acetobutylicum, an organism with a longstanding history in the commercial production of solvents, most notably 'butanol'. Butanol is an alcohol, which, like its counterpart ethanol may be used as a replacement for petrol as a fuel. Currently, the use of ethanol as a petrol additive is widespread in the developed world. The development of alternatives to petroleum as fuels is essential if we are to reduce our reliance on finite crude oil resources. However, butanol has many properties that make it far superior to ethanol. It has a higher energy content than ethanol, and its low vapour pressure and its tolerance to water contamination in petrol blends facilitate its use in existing petrol supply and distribution channels. Moreover, butanol can be blended into petrol at higher concentrations than existing biofuels, without the need to make expensive modifications to car engines. It also gives better fuel economy than petrol-ethanol blends. Despite their importance, our understanding of the biology of the Clostridium cell has lagged behind the data available for more recently evolved bacteria which 'breathe' oxygen. With the dawn of a new century the situation has changed. The complete genetic blueprint (genome sequence) of seven different Clostridium species has now been determined. The first was that of Clostridium acetobutylicum, a reflection of its commercial importance. It is the intention of this project to undertake an extensive analysis of the biological processes that take place when this Clostridium grows. In particular, we wish to understand the key events that occur during the transition between normal cell growth and the onset of both butanol production and spore formation. Our intention is to build a mathematical model of these processes such that the process may be recreated as a computer programme that mirrors the living cell. These aims will be progressed through a combination of disciplines (genetics, transcriptomics, proteomics, metabolomics, biochemistry, chemical engineering and mathematical modelling) deployed by a consortium of eleven European scientists, from three member states (Germany, the Netherlands and the UK). The current research programme will contribute to this broader effort by developing multiscale mathematical models for the various complex biological processes involved. The ability to predict more effectively the behavioural and metabolic response of clostridia will enable the more effective exploitation of C. acetobutylicum in the commercial production of butanol and as an anti-cancer delivery vehicle. It will also lead to a greater understanding of the biology of pathogenic species and, ultimately, to the development of more effective medical countermeasures.

The current research forms part of a SysMO project on the systems biology of Clostridium acetobutylicum and is focussed on the development of multiscale mathematical models for key processes involved, namely: (1) intercellular signalling and quorum sensing; (2) the regulatory networks associated with solventogenesis and sporulation; (3) the effects of redox state and glycosylation on solventogenesis; (4) stress response during transition. The main focus will be on the development and analysis of deterministic (primarily ordinary-differential-equation) models describing the above processes; stochastic effects will also be considered where appropriate. These new models will be the subject of extensive numerical simulations, together with parametrisation using, and verification against, experimental data (including that from partner teams). They will also be subject to sensitivity analyses and studies using asymptotic and dynamical-systems approaches in order to enhance their predictive capacity and to maximise the intuition they provide into the complex hierarchies of network interactions that are possible.