A novel technology to assess chronic toxicity in genetically diverse nematode populations - Project Abstract
The number of new products such as drugs, cosmetics and food additives introduced into the market is growing
and poses a significant challenge for risk prediction. Currently, vertebrate testing is the industry standard for
hazard assessment but has limitations including high costs, and the growing public and corporate sentiment
against using vertebrates for chemical testing. Importantly, current toxicity assessment does not incorporate
genetic diversity leading to failure of drug candidates and unintended risks to human sub-populations. The
celebrated invertebrate model C. elegans has the potential to fill this gap since thousands of genetically diverse
nematode populations are available. However, the main challenge is that chronic studies of chemicals in the
nematode model is still tedious, precluding large-scale toxicity testing in nematode populations. This proposal
aims to develop a high-throughput technology for chronic toxicity screening of diverse genetic populations in
adult C. elegans. The focus of our Phase I plan is to pursue chronic toxicity studies on select toxins and generate
foundational data highlighting the impact of genetic diversity, and subsequently scale the NemaLife technology
to enable large-scale genetic diversity screening.
AIM 1: To generate chronic dose-response data on toxins affecting diverse C. elegans strains. We will
test the effects of five toxins for which we know the variability in human and rodent responses. Animals will be
exposed to toxins daily, followed by scoring of survival, reproductive and neuromuscular health. About 1200
whole-life assays will be conducted with data acquired on 500+ animals per assay condition. We will generate
data that will define the rank-order of C. elegans toxin response vis-à-vis mammalian systems, optimize
phenotyping conditions for large numbers of strains per species, and define the amount of heritable variation in
toxin responses. These pilot data will validate the capabilities afforded by our screening platform.
AIM 2: To scale the throughput of NemaLife Technology for thousands of chronic toxicity assays.
Currently, NemaLife’s technology has a throughput of hundreds of chronic toxicity assays. However, given the
large number of toxins and vast library of genetic strains and wild isolates available, there is a significant need
to increase the throughput of our technology. Therefore, we will develop the technology infrastructure and
workflow to scale the throughput which includes multiplexing our approach, scale-up of chip fabrication and
streamlining data analysis. Technology development at the scale of thousands of whole-life toxicity assays in a
few weeks with readouts on animal death and neuromuscular impairments will be a major breakthrough in the
field opening up new business opportunities in toxicity testing in the drug and consumer industry.
