Periodic Reporting for period 4 - PHENOSPACE (Quantifying behavioural phenotype space: chemistry-to-gene screens and combination therapies)
Periodo di rendicontazione: 2021-06-01 al 2022-05-31
A central goal of precision medicine is to tailor treatments for individuals based on their genomic sequence. However, many common diseases are associated with mutations in multiple genes and drugs often interact with multiple targets, making it difficult to go from genome sequence to drug selection. Spontaneous locomotion in the nematode C. elegans provides a model to address fundamental questions about the mapping between chemical and genetic perturbation and complex phenotypes. We have developed the hardware and software for a high-throughput behaviour quantification platform and used it to measure changes in worm behaviour in response to treatment with small molecules and genetic perturbations. The result is a new view of a multidimensional phenotype space in a genetically tractable model animal that can be used to the predict targets of neuroactive compounds, discover new gene-behaviour associations, and suggest new indications for approved drugs. The platform enables new kinds of behaviour experiments at a larger scale than previously possible.
We have built a multi-camera imaging system with a field of view and resolution large enough to imaging hundreds of individual worms simultaneously from all of the wells of a multiwell plate (Barlow et al. (2022) Communications Biology). With five imaging rigs, we can perform almost 500 simultaneous worm tracking experiments. Using the system, a single researcher can investigate the effects of 10 000 compounds or bacteria in a single day. The system includes a bright blue LED system that we can use for stimulating worm locomotion which increases the range of observable phenotypes, increases our sensitivity to detect drug effects, and improves the accuracy of mode of action predictions (McDermott-Rouse et al. (2021) Molecular Systems Biology).
To analyse the output of the new system we have adapted Tierpsy Tracker (Javer et al. (2018) Nature Methods) to work with multi-well plates including the automatic detection and segmentation of multiple wells and for handling the associated metadata that links treatments with tracking data from videos (Barlow et al. (2022) Communications Biology). Once the data are tracked, we also developed a set of powerful and interpretable behavioural features that we use to summarise complex worm behaviour phenotypes as vectors of features that can be used in downstream clustering and classification tasks (Javer et al. (2018) Phil Trans R Soc B).
Finally, we have created a panel of worm models of Mendelian diseases and extracted their behavioural fingerprints. We were able to detect behaviour phenotypes for 85% of 40 disease models showing the sensitivity and scalability of our approach. We are now performing drug repurposing screens that may identify new candidate treatments for these underserved genetic diseases. We have also collaborated directly with clinicians to model diseases that they have diagnosed and characterised in rare disease patients (Rosenhahn and O'Brien et al. (2022) American Journal of Human Genetics).
To analyse the output of the new system we have adapted Tierpsy Tracker (Javer et al. (2018) Nature Methods) to work with multi-well plates including the automatic detection and segmentation of multiple wells and for handling the associated metadata that links treatments with tracking data from videos (Barlow et al. (2022) Communications Biology). Once the data are tracked, we also developed a set of powerful and interpretable behavioural features that we use to summarise complex worm behaviour phenotypes as vectors of features that can be used in downstream clustering and classification tasks (Javer et al. (2018) Phil Trans R Soc B).
Finally, we have created a panel of worm models of Mendelian diseases and extracted their behavioural fingerprints. We were able to detect behaviour phenotypes for 85% of 40 disease models showing the sensitivity and scalability of our approach. We are now performing drug repurposing screens that may identify new candidate treatments for these underserved genetic diseases. We have also collaborated directly with clinicians to model diseases that they have diagnosed and characterised in rare disease patients (Rosenhahn and O'Brien et al. (2022) American Journal of Human Genetics).
Our megapixel camera array tracker is a breakthrough in small animal behavioural screens. It opens the door to completely new kinds of behavioural experiments that were infeasible until now. It goes well beyond even the system I proposed in the Description of the Action. We can now screen up to 10 000 conditions in a single day which makes a genome-wide RNAi screen for behavioural phenotypes possible by a single researcher in a matter of weeks