The Inscripta Blog

November 17, 2020

Technology Networks: CRISPR Needs to Scale. Now.

Even the biggest fans of CRISPR have to acknowledge that the gene editing technique is not the easiest to use. (“Temperamental,” “tedious,” and “finicky” are some of the most common descriptors we’ve heard … at least among the ones we can repeat on a family-friendly site.)

For any kind of progress to be made, it’s essential to begin with an honest and open look at where things stand now. That’s the premise of a commentary article published in Technology Networks from Richard Fox, who most recently served as Inscripta’s Executive Director of Data Science. “The widespread enthusiasm we have seen [for CRISPR] should not be mistaken for equally widespread technical success,” he wrote. “CRISPR has been a challenge to implement due to a range of limitations.”

Right now, the labs that have been most successful with CRISPR are “extremely well-funded, with a wealth of dedicated CRISPR expertise on staff,” Fox pointed out. “Standing up high-capacity CRISPR pipelines requires skill and expertise in the design process used to build guide RNAs, nucleases, and cassettes.” Unfortunately, many labs — perhaps most labs — struggle to overcome the technical challenges associated with CRISPR and are forced to abandon this exciting technique.

Even for labs that do manage to get CRISPR working, though, problems remain. “Carefully tracking and monitoring edits made is critical for drawing conclusions from CRISPR-based experiments,” Fox wrote. “But reliable trackability becomes less feasible as scientists push boundaries in the complexity of edits, or in multiplex combinatorial editing.”

Scalability is another issue with today’s workflows. “I believe the most serious problem we face in today’s CRISPR workflows is that of scale,” Fox noted. “Failing to overcome today’s limited scalability will make it impossible to use this editing tool as we imagine to solve some of the greatest challenges facing our planet and our population.”

In the article, he walks through specific examples — such as recapitulating known mutations to establish function or performing large-scale protein mutagenesis — to show exactly how scale limitations are hamstringing scientists’ ability to move forward effectively. Instead of surveying the full scope of possible answers, “we test a small subset of possibilities, hoping that an ideal result just happens to fall within this narrow scope,” Fox wrote. “That’s gambling, not science.”

Real change would come from “dramatic increases in the size, number, types, and combinations of edits that can be made” in a CRISPR pipeline, he added. “The community needs reliable, workhorse methods that can produce high edit rates at tremendous scale, as well as the ability to introduce multiplex combinatorial edits for establishing sequence/function relationships.”

Here at Inscripta, we are committed to rising to that challenge. Our Onyx™ digital genome engineering platform is designed to deliver accurate results through an automated, scalable process that we believe will transform what’s possible with CRISPR workflows.