Systems biology of the Caenorhabditis elegans nervous system

Caenorhabditis elegans, or C. elegans, is a nematode worm, just a millimetre long, that lives in the soil, eating microbes, and is of no direct economic or medical importance. Nevertheless, this organism has qualities that make it a particularly suitable subject for experimental analysis and these have allowed very rapid progress to be made in studies of its biology. Furthermore, the remarkable level of conservation in biological processes across the animal kingdom have meant the many discoveries made with C. elegans are typically of direct relevance to the biology of other animals including man. The 2002 Nobel Prize for Physiology or Medicine was awarded for work on C. elegans and C. elegans was the first animal to have its genome sequenced, in research that pioneered the human genome sequencing project. C. elegans is one of the most important model systems in modern biological research. C. elegans was originally selected as a subject of study as the ideal model organism with which to understand animal development and animal behaviour. The premise was that a proper understanding of the complexity of biology depended upon a complete body of knowledge and the simplicity and ease of working with this species made the target feasible. This attitude led to the complete description of this animal's developmental cell lineage from fertilization to the adult, a complete ultrastructural description of this animal's entire nervous system and the absolutely complete determination of the sequence of the genome; none of which have yet been achieved for any other animal. The concept of needing knowledge of the entire system is the essence of the increasingly popular strategy of current biological research, now coined 'Systems Biology'. The other side of Systems Biology is theoretical modelling of biological processes. Mathematical modelling and computer simulations allow the complexity of the Biology to be clearly presented for better appreciation, to test how well we really understand the subject, to reveal gaps in our knowledge and to provide potential solutions to mechanistic failings in our views of biological processes. Such models are built upon the large bodies of experimental data that can now be generated in biology. Iteration, between experiment and modelling, allows refinement and development of our understanding of the Biology. Here we propose to study the Systems Biology of the C. elegans Nervous System. We will experimentally explore the mechanisms by which particular nerve cell identities are specified and we will elaborate computer simulations of the control of the locomotion in this worm. We will develop mathematical and computer models of the molecular mechanisms by which nerve cell fates are decided during development and modify the animal genetically to test the computer simulations of the co-ordination of movement. In this way we link between the computational and experimental approaches for the study of biology, to understand aspects of the complexities of both animal development and animal behaviour in this relatively simple animal, C. elegans. The links both between the biological topics (development and behaviour) and between the approaches (experimental and computational) are mutually facilitating. The scale of the task, because of the complexity of the subjects even in this simple animal, means we will be making only a contribution to the global efforts being applied with these aims, but the importance of the biological subjects we are studying, would make that contribution very significant.

C. elegans is one of the most important model systems for many aspects of biological research, but was originally selected as the ideal species with which to understand animal development and animal behaviour. The premise was that a proper understanding of the complexity of these biological topics depended upon a complete body of knowledge and that simplicity and tractability made the target feasible with this species. This is the very essence of what is now known as 'Systems Biology'. The C. elegans developmental cell lineage has been described completely from zygote to adult, there is a complete ultrastructural description of the nervous system and the genome has been completely sequenced. These bodies of knowledge, along with other large-scale data collections, can now provide the framework for detailed modelling of this animal's biology through which those targets of a full comprehension of an animal's development and behaviour can be realised. Transcriptional regulation of specific nerve cell fates will be defined and corresponding transcriptional regulatory networks models will be generated. Neural control of movement of C. elegans will be explored in mathematical and computer models of locomotion, to be tested in vivo. The understanding of the specification of particular nerve cell identities will be exploited in manipulation of the nervous system to check circuitry and neuronal models. The computer models of nervous system function will, in turn, constrain models of the mechanisms of nerve cell specification. Both aspects of the project depend on mathematical and computer modelling with experimental validation; 'in silico' representations would be repeatedly compared with experimental observations in an iterative process of refinement. The ultimate aim, to which this project would make a significant contribution, is an understanding of animal behaviour from the molecular level to the level of the whole organism.