A “village” approach that cultures cells from hundreds of people simultaneously could provide new insights into how genetics affect disease and drug treatment response, researchers say.
The village system involves culturing and differentiating cells from multiple donor individuals in a single dish, then analyzing using single-cell sequencing.
This captures the genetic differences between people, enabling large-scale studies of human organ systems that are normally inaccessible.
It also overcomes the need to obtain living tissue from the organs of donors and overcomes the limitations of studying cells from just a few individuals.
The findings, in Nature Communications, offer an elegant solution for scaling experiments to the large sample sizes needed for population-based insights.
“Our ‘village in a dish’ method provides a scalable platform to study the relationship between human genetics drug response at an unprecedented scale,” said senior author Professor Joseph Powell, PhD, who is director of Cellular Science at the Garvan Institute.
“This approach could accelerate the discovery of novel therapeutic targets and be used to identify which groups of patients will respond positively to specific drugs, he told Inside Precision Medicine.
For example, the team is currently screening drug compounds to test for cardiac toxicity using beating cardiac muscle cells derived from human induced pluripotent stem cells (hiPSCs).
These cells are generated by reprogramming somatic cells so they can differentiate into virtually any cell type in the human body, thereby providing a model system to study different cells in vitro.
“This work will allow us to guide personalised medicine for current therapies and speed up clinical trials for emerging therapies,” said Powell.
Until now, most population genetics hiPSC studies has involved using bulk RNA sequencing but this effectively averages the different expression of various cell types into a single measure.
Single-cell technologies provide a powerful solution for this challenge, as individual cells are investigated separately, and context-specific effects can be examined.
But while hiPSC cells are uniquely suited to study these context-dependent effects, cell lines from hundreds or thousands of individuals are required.
Village cultures, where multiple induced pluripotent stem lines are cultured and differentiated in a single dish, provide an elegant solution, the researchers say.
Their village approach retained key features from individual cultures, while efficiently scaling experiments to the sizes needed to offer insights into a population.
Cells could be assigned to an induced pluripotent stem line using single-cell sequencing and a large proportion of the variation in expression for many genes was due to line-specific effects rather than the village cultures per se.
The researchers conclude: “Village systems—paired with single-cell technologies—promise to revolutionise the field of population genomics of gene regulation.”
