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Finding function in novel targets: C. elegans as a model organism

Key Points

  • C. elegans is a model organism that has the potential to bridge the gap between in vitro and in vivo approaches by virtue of being amenable to high-throughput technologies while providing physiologically relevant data derived from a whole-animal setting.

  • Several features of C. elegans make it a powerful tool for the pharmaceutical industry. These include being easy to culture; undergoing rapid reproduction with a short generation time enabling large-scale production of animals; small size, which allows assays of more than a hundred animals in a single well of a 96-well plate; transparency, which enables the use of fluorescent markers to study biological processes in vivo; and cellular complexity — C. elegans is a multicellular organism that has many different organs and tissues.

  • Although in many cases a direct translation of human pathology into C. elegans phenotypes is impossible, C. elegans assays emulate certain aspects of human pathology. These help to elucidate the underlying molecular mechanisms and to deliver new approaches for therapeutic strategies, rather than recapitulating human disease pathology in every detail.

  • The benefit of C. elegans over mice or rats is its amenability to whole-animal high-throughput technologies. C. elegans investigations have already fostered a better understanding of the underlying mechanism for several diseases such as Alzheimer's disease, cancer, diabetes and depression.

  • WormBase, a database of C. elegans genetic and genomic information curated by a consortium of researchers, is an excellent resource for those wishing to use C. elegans as a model organism.

  • The availability of C. elegans RNA interference (RNAi) libraries has made it possible to carry out high-throughput genome-wide RNAi, which has shown success in identifying drug targets for diabetes and obesity.

  • C. elegans genetics can also be used to dissect the in vivo action of a drug, even if it modulates several targets. For example, antidepressant drug action can be studied in a functional serotonergic synapse within the context of a whole organism.

  • Although there are intrinsic limitations associated with C. elegans, such as the absence of some human molecular pathways in the worm, and the inability to model the complete pathophysiology of the disease, if the purpose and potential restrictions of the model are defined, the value of C. elegans in high-throughput, whole-organism screens becomes apparent.

Abstract

Despite its apparent simplicity, the nematode worm Caenorhabditis elegans has developed into an important model for biomedical research, particularly in the functional characterization of novel drug targets that have been identified using genomics technologies. The cellular complexity and the conservation of disease pathways between C. elegans and higher organisms, together with the simplicity and cost-effectiveness of cultivation, make for an effective in vivo model that is amenable to whole-organism high-throughput compound screens and large-scale target validation. This review describes how C. elegans models can be used to advance our understanding of the molecular mechanisms of drug action and disease pathogenesis.

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Figure 1: The serotonergic synapse of C. elegans.
Figure 2: Drug entry route into C. elegans.
Figure 3: Overview of the RNA interference supported target identification process.
Figure 4: Chemical genetics as a tool for target site identification.

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Correspondence to Titus Kaletta.

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T.K. is employed by Devgen NV. M.H. is a co-founder of Devgen NV. Both authors have shares in Devgen NV.

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DATABASES

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InParanoid

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Glossary

Chemical genetics

The investigation of the effect of a small molecule on an organism when a certain gene activity is increased or decreased; contrasts with chemical genomics studies, which look at the effect of a small-molecule compound on gene expression.

Cognate target

The protein to which a compound binds to mediate its physiological effect.

Porsolt forced-swim test

Rats that are forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture that can be readily identified. Antidepressants will delay onset of immobility.

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Kaletta, T., Hengartner, M. Finding function in novel targets: C. elegans as a model organism. Nat Rev Drug Discov 5, 387–399 (2006). https://doi.org/10.1038/nrd2031

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