Magnetic Cell Sorting + CRISPR = Faster Drug Discovery

By Deborah Borfitz

October 16, 2019 | A microfluidics device that uses magnetic labeling to sort one billion cells per hour, based on their molecular makeup, has the attention of biotechnology and pharmaceutical companies hungry for data on their favorite drug targets. The new platform pairs magnetic cell sorting with CRISPR-based gene-editing technology, which were developed by separate Medicine by Design teams at the University of Toronto (U of T), according to pharmacy professor Shana Kelley.

A study (https://doi.org/10.1038/s41551-019-0454-8) published in a recent issue of Nature Biomedical Engineering describes how microfluidic cell sorting (MICS) was used in conjunction with CRISPR screening to find a protein (QPTCL) that can be targeted to indirectly drug the "don't eat me" immune checkpoint protein CD47, says Kelley. The next step is to scale up the technology to do multiple screens in parallel to look for new targets for cancer immunotherapy drugs and "undruggable" proteins involved in tumor progression.

MICS, an innovation of Kelley's lab team, is a chip-like device the size of a credit card that does the needle-in-a-haystack cell sorting. Tiny magnets are engineered to bind to the target protein, so cells end up in a collection channel corresponding to the number of magnetic particles sprinkled on their surface, she explains. The particle count is a proxy for protein amount in the cells.

CRISPR allows scientists to "knock out one gene per cell in a billion-cell mixture… but maybe only 50 of them are doing something interesting that would tell you about a drug target," Kelley says. Fluorescent labeling is typically done to find those rare cells one at a time, but that can take a couple weeks. "We have a superhighway and channels for them to be processed through, so it speeds things up by many orders of magnitude."

Invention of the platform is credited to the multidisciplinary collaboration made possible by Medicine by Design, a leading center that uses engineering design principles and quantitative biological modelling to accelerate breakthroughs in regenerative medicine and cell therapy. It launched in 2015 with a $114 million federal grant, the largest in the U of T's history.

Kelley says she kept bumping into cellular and biomolecular research professor Jason Moffar at meetings because of their mutual involvement with Medicine by Design. Eventually the idea arose to combine her team's cell-sorting device with his team's gene-editing technology. "It speaks to the power of just getting people in the same room."

A new multi-lab collaboration, called the Phenotypic Genomic Screening at Scale (PEGASUS) project, will advance the technology to quickly interrogate a broad range of therapeutic targets at the same time, says Kelley. Financial support is coming from Medicine by Design on the regenerative medicine front, where MICS will help find the regulators of stem cell differentiation and harvest specialized cell types of interest for therapeutic use.

Researchers are actively looking for partners as well as funding to pursue drug discovery for oncology. "We think we'll be up and running in the next six months, with data available from the first large-scale studies in the coming year," Kelley says.

Interest in the MICS platform has been particularly high among biotech and pharma companies, some of whom are looking to repurpose drugs already being used in the clinic for other cancer types, she says. "With our ability to do these large-scale screens, we should be able to develop a pipeline of new targets for them." Groups focused on treatments for rare conditions and diseases with a known phenotype, but an unknown genetic basis, have also been eying the technology.