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Innovation begets innovation: Student initiative evolves into patented solution

From undergraduate education to patent and biotech startup, cutting-edge research recently published in Nucleic Acids Research from the Hill lab demonstrates how BYU mentorship empowers students to innovate and achieve.

“I actually think the mentorship aspect is the best story here,” says Dr. Jonathon Hill, the senior author of the study and an associate professor of cell biology. “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.”

Dr. Jonathon Hill and his student Joshua Yates

Hill wanted to discover genes involved in heart development, but the chemicals typically used for these 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.

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. 

Essentially, “a library is a collection of different molecules,” says Joshua Yates, the former undergraduate and graduate student who carried out the study. “And CRISPR is a way to of modifying a gene, so a ‘CRISPR library’ is basically a collection of molecules that can modify different genes.” 

When this project started in 2015, CRISPR libraries could already be synthesized by designing the sequences on a computer and ordering them from a company. However, this process could cost up to $5,000–10,000, 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.” Dr. Hill tasked some of the undergraduate students working in his lab with the project. The students found that the process took approximately three days—considerably less than the originally proposed four weeks—and consisted of several steps to create the final product.

“We were using this process, but it was still slow and difficult to carry out,” Yates says. “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 CRIPSR 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 knew how to condense the protocol. “By the end, I was like, ‘Ah, I see it now,’” Hill shared.

The key innovation was to modify a portion of the CRISPR complex, called the sgRNA. However, it was essential that the modifications did not hinder CRISPR function. The team ended up testing approximately 20 versions of the protocol before getting it to work. Yates eventually turned the project into a master’s degree in Physiology and Developmental Biology, working under Dr. Hill’s mentorship.

“There were several times when we were going through our 20 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 the I was thinking about how this thing wasn’t working the entire time.”

In the end, Yates cut the long three-day protocol down to 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.”

Joshua Yates in a lab

Almost five years after the project’s inception, this 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 previous methods by utilizing the host’s DNA to create custom libraires and magnetic beads to speed up the process. These innovations drastically reduce the time and resources spent and massively enhance 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,” laughs Yates.

CRISPR libraries make forward-genetic screens less dangerous and more targeted and efficient. However, to this day, synthetically generating CRISPR libraries is still expensive and requires extensive bioinformatic knowledge. All this makes them less accessible to scientists without a background in bioinformatics or large amounts of research funding.

“Using SLALOM is really cool because now scientists don’t need bioinformatic skills to build a library. You can just build it using biology instead of a computer,” Yates says. “Being able to just do it on the benchtop will hopefully open up CRISPR technology to scientists who maybe wouldn’t have had access to it before.”

“We feel like innovation in the field has been hindered by how difficult it is to make custom libraries,” Hill adds. “From here, we think people are going to come up with novel uses for the technology, so we’re excited to see what ideas others come up with. We overcame this big hurdle that’s holding the field back, so now others can run with it. Innovation begets innovation.”

Together, Yates and Hill have successfully applied for and obtained a patent for their technology. Yates, now the co-founder and CEO of a startup to commercialize the technology, has a prototype of the SLALOM kit. He is in the process of ordering more kits for sale and research use.

Going back to the mentoring story, Hill says, “In this case, mentoring wasn’t just someone working in my lab. This was someone working as a partner with me on their own idea to take it all the way to completion. And I hope that more students can catch on. You’re not just a robot in the lab. You’re an active part of the research. And that, I think, is what sets BYU apart. For an undergraduate to take their own idea to the professor and say, ‘Will you work with me on this?’ It’s a different paradigm, one you don’t see anywhere else.”

Yates adds his voice to Hill’s. “I think what undergraduates are exposed to at BYU is very unique,” he says. “Given the opportunity to try to modify the CRISPR molecules as an undergrad? That’s not an opportunity a lot of students get. The undergraduate research experience here is phenomenal and is there for anybody who wants it.”