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Impact Magazine

From Partnership to Patented Research: Undergraduate Student Innovates Gene-Editing Tools

It’s not every day that an undergraduate student approaches you with an innovative idea that significantly impacts the field and leads to developing a patented product, a startup company, and published research,” says Jonathon Hill, an associate professor of cell biology at BYU. “[But] I actually think the mentorship aspect is the best story here.”

In 2015, Hill was researching genes involved in heart development, but the chemicals typically used for these genetic screens were highly toxic and difficult to work with. To avoid working with these chemicals, he looked into synthesizing a CRISPR library to alter the genes.

A student examining samples in a lab.
Photo by BYU Photo

At the time of the project’s inception, CRISPR libraries could be synthesized by designing the sequences on a computer and ordering them from a company. However, this process could cost up to $10,000, take approximately four weeks in turn-around time, and require a significant knowledge of bioinformatics.

“We couldn’t afford to synthesize a CRISPR library,” Hill says. “Another colleague pointed me to an article that had just been published with a method for enzymatically generating CRISPR libraries, so we decided to try it out.”

The undergraduate students working in Hill’s lab found that the new method took approximately three days, considerably less time than the originally proposed four weeks, and consisted of several steps to create the final product.

However, the method “was still slow and difficult to carry out,” says Joshua Yates, one of the undergraduate cell biology students from Hill’s lab. “I started looking at the shape of the CRISPR molecules, how they fit together, and decided that it might be possible to tweak things a little bit to create CRISPR libraries more quickly.”

Yates approached Hill with his idea. “Josh came to me and said, ‘I can do this in four steps and a couple of hours,’” Hill said. “My initial response was, ‘No, you can’t, what are you talking about? I looked at the protocol, and it takes three days.’” But after Yates brought in a stack of scientific papers, including some that looked at the structures of the CRISPR protein complexes, and walked Hill through the process step by step, it was clear that Yates had done his research and saw a way to condense the protocol.

Infographic about CRISPRs on a blue background. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. It is a powerful gene-editing tool used to alter DNA sequences and gene function. The CRISPR system was originally discovered as an immune defense system in bacteria. Since then, it has been adapted for laboratory use to allow researchers to make specific changes in DNA.

The key innovation was to modify a portion of the CRISPR complex, specifically the sgRNA. However, it was essential that the modifications did not hinder CRISPR function. The team ended up testing approximately twenty versions of the protocol before getting it to work. Yates carried the project into his master’s program in physiology and developmental biology, working under Hill’s mentorship.

“There were several times when we were going through our twenty different iterations where I thought that we had reached an insurmountable obstacle,” Yates reflects. “And there were several times where things just stopped working, and I had no idea why. I went on a little vacation once and it ruined my whole trip because I was thinking about how this thing wasn’t working the entire time.”

In the end, Yates successfully cut down the long three-day protocol to just three hours with his modifications to the CRISPR molecules.

“This was pretty close to the original goal, I think,” Hill says. “I mean, Josh initially said four steps—it’s five. He said a couple of hours—it’s about three or four, because we had to add a couple of cleanup steps. But really, in the end, I’d say we met our engineering goal.”

Almost five years after the project’s inception, the research was published in Nucleic Acids Research. The article describes the new technology Yates and Hill created to enzymatically generate CRISPR libraries, which they named SLALOM (sgRNA Library Assembly by Ligation on Magnetic beads). This technology improves on previous methods by utilizing the host’s DNA to create custom libraries and magnetic beads to speed up the process, drastically reducing the time and resources spent, and massively enhancing the accessibility of the technique.

“I think it’s a lot about democratizing forward genetic screens,” Hill states. “A typical library can be synthesized by a company, but it can cost you up to $10,000 and four weeks. Using our method, it’s $100 and less than a day.”

“Well, specifically, we got it down to three hours,” Yates says.

Overall, CRISPR libraries make forward-genetic screens less dangerous, more targeted, and more efficient. However, still today, synthetically generating CRISPR libraries is expensive and requires extensive bioinformatic knowledge— making the libraries less accessible to scientists without a background in bioinformatics or without large amounts of research funding.

Hill and Yates believe innovation in the field has been hindered by these roadblocks. Their new technology, SLALOM, helps solve these problems as an approachable and inexpensive advancement. “You can just build it using biology instead of a computer,” Yates says. “Being able to do it on the benchtop will hopefully open up CRISPR technology to scientists who maybe wouldn’t have had access to it before.”