A range of in vivo animal models are currently used to examine emetic and taste aversive side effects of novel chemical entities in the development of medicines, for orally ingested compounds such as food additives, and for compounds designed to deter human consumption. In the case of emesis (nausea and vomiting), this effect is amongst the most common side effects of current drugs and can cause a dose-limiting toxicity and be responsible for reduced patient compliance. These studies can cause animal suffering, are time consuming and costly. There is therefore a pressing need to develop alternative non-animal models that may reduce or replace these adverse animal experiments.
Professor Robin Williams at Royal Holloway London University has shown that a simple biomedical model, the social amoeba Dictyostelium, shows a concentration-dependent response to a range of emetic, aversive and bitter compounds, suggesting it will provide an effective medium throughput screening model in this role. Through the CRACK IT Solutions scheme, he has secured support from GlaxoSmithKline (GSK) and Syngenta who will supply chemicals for which concentration-response data regarding nausea, vomiting or taste aversion (bitter tastants) is available from both animal models and human volunteers. Using these compounds, this project will develop and validate the Dictyostelium as a model for reducing in vivo animal experimentation in the selection and development of novel chemical entities with reduced emetic liability and improved palatability.
Full details about this CRACK IT Solution can be found on the CRACK IT website.
The project successfully developed a medium throughput screen for analysing bitter compounds using Dictyostelium. Various physical behaviours (speed of movement, shape, protrusion number) of Dictyostelium undergoing random movement were video recorded and analysed by computer-generated cell outlining. Analysis of the eight compounds suggested by GSK for these experiments provided a range of potencies which were validated against bitter potency in established human, rat and electronic tongue models. The rank order for these substances in all models closely resembles data derived from Dictyostelium for seven of the compounds, suggesting that Dictyostelium may provide a suitable animal replacement model in bitter tastant perception.
The project has led to significant investment by GSK in funding a PhD studentship to further investigate the use of Dictyostelium as a replacement model in bitter tastant research. The long term outcome for this project will be the reduction of adverse in vivo testing of tastants and drugs using animal models. The successful development and employment of Dictyostelium as a model will also likely reduce the development of compounds that will fail in late drug/food stuff development.
The team has further initiated a small experiment with Syngenta to examine one of their compounds using the Dictyostelium model and are currently exploring the possibility of engaging more industrial partners in validating the model further.
Cocorocchio M et al. (2016). Bitter Tastant Responses in the Amoeba Dictyostelium Correlate with Rat and Human Taste Assays. ALTEX 33(3), 225-236, doi: 10.14573/altex.1509011.
Contractor(s)Professor Robin Williams
Royal Holloway University of London