clear how valproic acid works, stifling the design and testing of new compounds. Epilepsy researchers are generally looking for new drugs that block the elevated electrical activity that leads to seizures. Standard models for seizure and epilepsy research involve stimulating and recording electrical activity in rat neurons in slices of (rat) brain kept alive in a dish, or in whole live animals (normally rats). However, there is increasing social concern about the use of animals in research, reflected in changing funding and legislation (eg Home Office licences). As a result there is a greater adoption of the ‘3Rs’ approach (reduction, replacement and refinement) in biomedical research to minimise animal use. Research in this area is costly (US$850m per drug), time consuming (clinical development and approval takes on average 8.8 years) and has a low success rate, 8.2% (Miller, 2010). A new model Dictyostelium discoideum (Fig. 2, over) is a social amoeba occurring naturally in the leaf litter of forest floors in temperate climates (Williams et al, 1996). It survives by consuming microorganisms and multiplying by binary fission. Its common name (social amoeba) comes from its unusual behaviour when exposed to starvation conditions: the normally single-cell amoeba move towards a single point to form a mound of cells, triggering cells to differentiate and form a multicellular fruiting body over a 24-hour period. This life cycle has enabled researchers to closely examine the cellular and molecular processes
involved in cell movement and differentiation, and subsequently to transfer these discoveries to mammalian systems (eg immune cell movement). Dictyostelium has also recently proven an excellent model for understanding molecular aspects of altruistic behaviour, various aspects of disease signalling and infection, and as a model for exploring the cellular functions of a range of proteins. A series of important characteristics gives rise to the diverse range of experimental uses for Dictyostelium. This includes the ability to rapidly delete a target gene – since the organism is haploid (one set of chromosomes), mutants lacking the encoded protein can be readily constructed. Because the single cells can then be isolated and propagated (Fig. 1, left), genetically pure cultures of these mutants can then be used in research. Conversely, the expression of any gene can be elevated, creating cells with an increased level of a defined protein and, again, genetically pure cultures of these mutants can be created. These two approaches
BIOgraphy
Professor Robin Williams is head of the Centre for Biomedical Sciences at Royal Holloway University of London, where he is professor of molecular cell biology. He first used Dictyostelium in 1998 to explore bipolar disorder drugs. He has set up a research group to explore the molecular mechanisms of valproic acid.
Research organisations increasingly attempt to ‘reduce, replace or refine’ research on animals.
enable researchers to rigorously analyse the function of defined proteins in cell function or in development (Fig. 3, over). Dictyostelium can also be used to quickly and easily monitor the effect of therapeutic drugs, or other chemicals, where the behaviour of cells can change rapidly following drug exposure, and this can be used to dissect the biochemical and molecular mechanisms controlling how the drug works. What has often held back the wider application of Dictyostelium as a model in drug related research is the concern that discoveries are unlikely to successfully translate to more complex systems (such as the mammalian brain during seizures). However, in recent years, a range of studies has highlighted the use of this amoeba in the analysis of how valproic acid works in preventing seizures and therefore contributed to the development of improved treatments. Epilepsy’s holy grail To analyse how epilepsy treatments control seizures using a model system, the first question to ask is ‘does the antiepileptic drug have an effect on your model?’ In Dictyostelium cells, the formation of the fruiting body is blocked at concentrations of valproic acid
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