Animal testing in the research-based pharmaceutical industry has been reduced in recent years both for ethical and cost reasons. However, it is still a staple when it comes to discovering new compounds directed at improving human health.
Recently, I have come across more and more researchers who are looking for the most efficient way to move forward in the discovery of new compounds that will improve human health. Their goal is to rapidly:
i) identify the most promising compounds;
ii) understand their mechanisms of action;
iii) test their efficacy and/or toxicity in a living animal to quickly and more confidently move to commercialization or clinical trial.
Most of them have relied on mice or mammalian cells, but many are concerned about the cost and time of such approaches at an early stage. As one researcher told me, “mammalian cell lines are very difficult to work with and they make everything more expensive. It’s a time issue too.” Live mammals, even more so. These scientists know that the microscopic soil nematode C. elegans, on the other hand, has built a solid reputation as a powerful genetic model organism. Highly tractable, with a 2-week life cycle, C. elegans provides an attractive alternative for devising and streamlining efficient pre-clinical testing.
Disease Modeling and Drug Testing
“Mammalian disease models offer in vivo opportunities and extensive similarity to the human brain, but testing the therapeutic/health improving value of small molecules in mammalian model systems is extremely expensive and requires time-consuming experimental designs that can be prohibitive”.1 “Much of the essential genes involved in disease presentation are highly conserved from yeast to humans. For instance, when one restricts the comparison to the 6460 genes known to be associated with genetic disease (1/3rd the human genome), clear similarity (orthology) to C. elegans occurs for 79% of the human disease genes (ClinVar database). This high degree of interspecies conservation between worm and human has recently become more recognized and appreciated for use in disease biology understanding”.6,8,9,15
“A number of practical advantages […] such as short lifespan allowing rapid in-vivo testing, conservation of disease and stress response pathways, availability of mutant and transgenic strains, and wealth of biological information, have led to the increased use of C. elegans in toxicological studies.” 5
“Unlike toxicity testing using cell cultures, C. elegans toxicity assays provide data from a whole animal with intact and metabolically active digestive, reproductive, endocrine, sensory and neuromuscular systems. Toxicity ranking screens in C. elegans have repeatedly been shown to be as predictive of rat LD50 ranking as mouse LD50 ranking. Additionally, many instances of conservation of mode of toxic action have been noted between C. elegans and mammals. These consistent correlations make the case for inclusion of C. elegans assays in early safety testing and as one component in tiered or integrated toxicity testing strategies, but do not indicate that nematodes alone can replace data from mammals for hazard evaluation.” 10
“Positive predictive power of C. elegans for toxicological research has been shown. For example, one study demonstrated that 89% of compounds compromising egg viability in the worm also have known developmental effects in mammals12, while a study of 47 compounds associated with mammalian reproductive toxicity showed up to 69% concordance between C. elegans data and ToxRefDB mammalian data13. In a more extensive study, toxic effects associated with exposure of C. elegans to over 900 chemicals were compared with ToxCast data from zebrafish, rats and rabbits.14
The authors found concordance of C. elegans data with data from rats and rabbits of between 45 and 53% across a range of doses, which is only slightly lower than the concordance between rat and rabbit data (58%).” 11
The nematode C. elegans is accepted by the scientific and pharmaceutical community as a model system to study the underlying molecular mechanisms involved in neuronal health “because of it’s well-characterized and easily accessible nervous system, short generation time (~3 days) and lifespan (~3 weeks), tractability to genetic manipulation, distinctive behavioral and neuropathological defects, coupled with a surprisingly high degree of biochemical conservation compared to humans. Remarkable similarities exist at the molecular and cellular levels between nematode and vertebrate neurons. For example, ion channels, receptors, classic neurotransmitters such as acetylcholine, glutamate, γ-aminobutyric acid (GABA), serotonin, and dopamine (DA), vesicular transporters and the neurotransmitter release machinery are similar in both structure and function between vertebrates and C. elegans. Importantly, the impact of different environmental and genetic changes such as exposure to small molecules on the health, survival and function of the nervous system can be readily studied in C. elegans in-vivo.” 1
“C. elegans is well-established as an aging research model and has enabled the identification of pathways influencing aging, such as the insulin/IGF-1 (IIS) and mTOR pathways, which are evolutionary conserved in mammals. […] A number of recent studies have identified microbial pathways affecting aging and longevity in C. elegans, introducing this model as a viable way to understand the role of the gut microbiota in health and aging.” 3
Studies on C. elegans microbiomes demonstrate that bacteria are able to enhance growth of nematode populations, as well as resistance to biotic and abiotic stressors, including high/low temperatures, osmotic stress, and pathogenic bacteria and fungi. The characteristics of these effects, their relevance for C. elegans fitness, the presence of specific co-adaptations between microbiome members and the worm, and the molecular underpinnings of microbiome-host interactions represent promising areas of future research, for which the advantages of C. elegans as an experimental system is of high value.3,4
The high tractability and fast life cycle of C. elegans makes it a prime model for early in-vivo testing and drug discovery. As NemaMetrix is working with clinicians and pharmaceutical companies, we have simplified and accelerated their access to rapid, reliable insight on human health. We do so by providing specific strains made to order – such as humanized worms that express human genes and/or disease variants – or simply by testing new compounds for proof of concept and/or peace of mind prior to hefty investments into one discovery pipeline or the other. C. elegans has already facilitated the identification of potential novel therapeutics, and the combination of genetic models with screening platforms continues to be a very efficient strategy for therapeutic drug discovery for aging and human diseases.
- Chen X. et al (2015); Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases Chem Cent J. 2015; 9: 65.
- Sonnhammer, E.L. and Durbin, R. (1997); Analysis of protein domain families in Caenorhabditis elegans. Genomics 46, 200–216
- Ezcurra M., (2018); Dissecting cause and effect in host-microbiome interactions using the combined worm-bug model system. Biogerontology 19(6): 567–578
- Zhang et al., (2017); Caenorhabditis elegans as a Model for Microbiome Research Front. Microbiol. 2017; 8:485.
- Boyd et al (2010); Caenorhabditis elegans as a model in developmental toxicology. Methods Mol Biol. 2012; 889: 15–24.
- Golden A. (2017); From phenologs to silent suppressors: Identifying potential therapeutic targets for human disease. Mol Reprod Dev. 2017 Nov;84(11):1118-1132
- Apfeld J et al. (2018); What Can We Learn About Human Disease from the Nematode C. elegans? Methods Mol Biol. 2018;1706:53-75.
- Wang J et al. (2017); MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome. Am J Hum Genet. 2017 Jun 1;100(6):843-853.
- Wangler, M. F. et al. (2017); Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research. Genetics. 2017 Sep;207(1):9-27.
- Piper Reid Hunt (2017); The C. elegans model in toxicity testing. J Appl Toxicol. 37(1): 50–59.
- Xiong H. et al. (2017); An enhanced C. elegans based platform for toxicity assessment. Sci Rep. 2017 Aug 29;7(1):9839. doi: 10.1038/s41598-017-10454-3.
- Harlow, P. H. et al. (2016); The nematode Caenorhabditis elegans as a tool to predict chemical activity on mammalian development and identify mechanisms influencing toxicological outcome. Sci. Rep. 6, 22965 (2016).
- Allard, P. et al. (2013); A C. elegans screening platform for the rapid assessment of chemical disruption of germline function. Env. Heal. Perspect 121, 717–724 (2013).
- Boyd, W. A. et al. (2016); Developmental Effects of the ToxCastTM Phase I and Phase II Chemicals in Caenorhabditis elegans and Corresponding Responses in Zebrafish, Rats, and Rabbits. Env. Heal. Perspect. 124, 586–593 (2016).
- Hopkins, C. (2019); Worming into Relevance – Human disease models in the C. elegans nematode. NemaMetrix.com