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Accelerating Drug Discovery for Diseases of Ageing:In Vivo High Throughput Screening with C. elegans

In an era where rapid drug discovery is crucial, high throughput screening (HTS) emerged in the 1990s as a significant development, allowing for the swift and effective identification of active compounds and deeper insights into biological pathways. This process involves testing large libraries of compounds against biological targets to identify potential drug candidates. It relies on robotic automation and the use of standard format 96, 384 or 1536 well plates to screen tens of thousands of compounds per day.


Despite its transformative impact, current HTS methods face significant challenges in studying complex in vivo responses and age-related diseases. This article explores the potential of using C. elegans as a scalable and effective in vivo model for high throughput drug discovery in these therapeutic areas.

The Uses and Challenges of Traditional Models in HTS


In Vitro Screening
In vitro screening methods are widely used due to their cost-effectiveness and suitability for initial compound screening. These methods involve testing compounds in biochemical assays or with cultured cells to identify those that exhibit desired biological activity. However, in vitro models have limitations. They often fail to replicate the complex interactions that occur in living organisms, making it difficult to predict the efficacy and safety of compounds in humans. This limitation is particularly problematic for studying age-related diseases and other conditions where the cellular environment plays a critical role.


Traditional 2D cell cultures, for instance, do not adequately mimic the three-dimensional architecture and microenvironment of tissues, which can significantly influence cell behaviour and drug responses. Moreover, cells in culture do not experience a comparable ageing process to whole organisms, which further limits their utility in age-related disease research.


The only cells that show ageing are human primary fibroblasts and they are difficult to obtain in high numbers and vary between individual donors. Using these cells fails to replicate the systemic and tissue specific ageing processes observed in whole organisms. This discrepancy can lead to misleading results when evaluating the efficacy of compounds to interfere with chronic diseases of ageing.


3D cell culture techniques have been developed to address some of these limitations by better replicating in vivo conditions. These advanced models incorporate more than one cell type and extracellular matrices to create a more physiologically relevant environment. However, despite their advantages, 3D cultures are less amenable to HTS, mostly because consistent establishment of cultures and microscopy is challenging in multi-well plates to the level required for large throughput screening.

A related development is organoids, which are mini clusters of cells that mirror many properties of organs. Scaling this approach to HTS is possible but constrained by issues of consistently sorting large numbers into multiwell plates, and then performing microscopy on them.

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