CAENORHABDITIS ELEGANS

Routine chemical toxicity testing costs millions of Euros a year per chemical tested and results in the deaths of an extremely large number of laboratory animals. In recent years there has been a shift away from animal testing, due to cost, pressure from society and ethical considerations, towards non-animal testing methods. By using a whole systems approach, such as with the microscopic nematode Caenorhabditis elegans (C. elegans), a more complete understanding of the toxic potential of a chemical can be achieved. C. elegans is a well characterised roundworm which are significantly similar to humans in terms of their genetic make-up and cellular processes. Strikingly, C. elegans has many similar tissues to mammals, including intestine, skin and neurones. Indeed, where mammals have over 16 billion neurons, C. elegans has just 302, which enables investigations to be undertaken at the level of single neurons. Additionally, the worms are easily and cheaply grown in the laboratory and are not subject to animal welfare acts. Consequently, C. elegans is well suited to the 3R principle of toxicity screening (i.e. the Replacement, Reduction and Refinement of animal testing).


 

Our research in the BioCentre

We use the microscopic nematode Caenorhabditis elegans as a model system to understand the molecular mechanisms that underlie toxicity. In addition, we also use the nematode as a whole systems-biology approach for screening drugs and compounds for health, anti-obesity, anti-diabetic and longevity effects.

Obesity

By using a medium-throughput screening method designed in-house, we screen compounds and fruits for their ability to reduce fat (i.e. have anti-obesity properties). Using RNA interference, it is possible to identify the molecular mechanism of action of the compound/fruit. The results are then used to perform more informed clinical trials.

Toxicity testing

Chemicals must be tested as part of the R&D process to pre-screen compounds for toxicity. At the BioCentre, we screen compounds for a variety of standard end-points, including fertility (see graph), lifespan and neuronal development. Due to the high level of homology with humans, at the level of genes and proteins, as well as in basic mechanisms and functions, C. elegans can be used to dissect the molecular pathways through which compounds exert their effects. 

Cancer

We have developed a third year course at the HAN where students use our C. elegans cancer model (Hughes et al. 2013) to investigate the genetic basis of the stem cell-like seam cell hyperplasia. Research in the BioCentre also uses this model to investigate the use of natural compounds, e.g. Taxol to treat cancer, and also investigating robustness following environmental stress using the seam cells as a readout. 

Future

We are currently working with the HAN Engineering Department to develop novel medium-high throughput screening tools to enhance our research. In addition, we are pursuing research into diabetes and neurodegenerative diseases.
 

Selected publications

  •  Mihaylova, Y., Abnave, P., Kao, D., Hughes, S., Lai, A., Jaber-Hijazi, F., Kosaka, N. and Aboobaker, A. 2018 Conservationof epigenetic regulation by the MLL3/4 tumour suppressor in planarian pluripotent stem cells Nature Communications 9:3633
  • Hughes, S. and Woollard, A. “RUNX in invertebrates” 2017 Chapter 1 in RUNX proteins in Development and Cancer, part of the Advances in Experimental Medicine and Biology Series published by Springer, ISBN 978-981-10-3231-8
  • Hughes, S., Brabin, C., Appleford, P.J. and Woollard, A. (2013) CEH-20/Pbx and UNC-62/Meis function upstream of rnt-1/Runx to regulate asymmetric divisions of the C. elegans stem-like seam cells. Biology Open 2(7):718-27
  • Hughes, S., Bundy, J., Want, E., Kille, P. and Sturzenbaum, S.R. (2009) The metabolomic responses of Caenorhabditis elegans to cadmium are largely independent of metallothionein status, but dominated by changes in cystathionine and phytochelatins. Journal of Proteome Research 8(7):3512-3519
  • Hughes, S. and Sturzenbaum, S.R. (2007) Single and double metallothionein knockout in the nematode C. elegans reveals cadmium dependent and independent toxic effects on life history traits. Environmental Pollution 145:395-400

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