Owen Fenton is exploring the possibilities of genetic medicine

The NC TraCS K12 scholar is studying how targeted genetic therapies could help solve an array of diseases and conditions.

The human genetic code contains the instructions needed to make a vast array of molecules, each with a role in our body's complex machinery. The genes HBA1, HBA2, and HBB, for example, contain information our cells use to make hemoglobin A, a protein that enables our red blood cells to carry oxygen. The gene KRT1 produces keratin 1, one of the proteins that help keep our skin damage-free. And a whole smattering of genes lay the framework for our body to produce antibodies, which we use to counter infections.

In total, around 20,000 protein-coding genes are written into the human genome, keeping us alive and making us who we are. And to Owen Fenton, an assistant professor of pharmacoengineering and molecular pharmaceutics at the University of North Carolina's Eshelman School of Pharmacy, those 20,000 genes also provide an opportunity for improving people's health.

Fenton's work aims to employ mRNA, a substance used by cells to translate genes into proteins, to treat a variety of diseases. And now, as a K12 scholar with the North Carolina Translational and Clinical Sciences (NC TraCS) Institute, Fenton is studying how we might create, deliver, and activate mRNA as medicine—using the fundamental basis of our biology to search for answers to some of the major medical challenges of our time.

"Something that's always attracted me to the medical development field is this idea that, maybe someday, hopefully not too far away, you can help one person," Fenton says. "And I think that's something that's very attractive with mRNA—it opens up avenues that maybe don't exist with classical molecules or classical biologics."

When our body wants to create a protein, an enzyme called RNA polymerase reads the section of our DNA that codes for that protein. The RNA polymerase creates a complementary sequence of that DNA called pre-mRNA, which is quickly transformed into mRNA, a single strand of genetic code that our cells can use to build a protein from scratch. For researchers like Fenton, the excitement comes from the possibility of being able to employ a patient's own protein-creation abilities to treat disease.

Say, for example, a person wasn't naturally producing enough of a certain protein. If a researcher could give that person the mRNA that codes for the protein they were missing, the person's cells could be prompted to produce more of the protein in question, alleviating whatever symptoms might be caused by the protein deficiency. Researchers could also use mRNA to prompt our cells to create proteins such as harmless segments of a virus, which could spur our immune system to produce antibodies that know how to fight off that virus.

Fenton's work centers around the fundamental research needed to make this technology work, and he's been fascinated with these kinds of research questions for a long time. His love of education, he says, came from his mom, who worked in education. Fenton's dad was a professional ice hockey player for teams like the Los Angeles Kings, Calgary Flames, and San Jose Sharks, who later started working as an ice hockey scout, a field Fenton's brother later joined as well.

"And really it's not that different from a lab, right?" Fenton says. "They go to a game and they're very analytical, they take notes, they synthesize hypotheses."

When he started doing lab work as an undergraduate at the College of the Holy Cross in his native Massachusetts, Fenton studied chemistry. He continued on that path for his PhD at MIT, focused on the synthesis of complex molecules—but soon, he started to feel an itch to get into the medical space, where he values an interdisciplinary focus.

"If we're trying to develop a new drug, your cells aren't saying 'Hey, this is a biology question' or 'This is a chemistry question'," Fenton says. "No—you have to integrate all of these skillsets."

After a quick stop at the National University of Singapore, Fenton joined UNC in late 2021, and now works with a diverse team of researchers and collaborators, with backgrounds in chemistry, engineering, and biology. Together, they focus on the possibility of using mRNA as a medical tool, including a lot of work with "lipid nanoparticles," or tiny blobs of lipids that scientists use to package mRNA and send it around the body.

If you imagine your bloodstream is just this really complex, interconnected network of highways and streets, we need to actually make sure that delivery is going down the right roads and finding the right town, the right house, the right mailbox.

Lipid nanoparticles solve one of the major challenges associated with the concept of mRNA-based medicine—mRNA is incredibly fragile. In the body, mRNA only needs to travel from a cell's nucleus to its cytoplasm. But to be used as a therapy, mRNA needs to travel from a syringe outside the body, through the bloodstream, and into a cell. If you tried to send the mRNA on that journey on its own, it would deteriorate well before reaching its destination, rendering it useless. But, as it turns out, if you encase that mRNA within a tiny sac of lipids, it can be protected as it travels.

Fenton says to imagine the lipid nanoparticle as a delivery truck, carrying the mRNA to a cell. But that brings up another challenge. To use mRNA as a form of precision medicine, you also need to make sure that the lipid nanoparticle can bring the mRNA to the right part of the body.

"If you imagine your bloodstream is just this really complex, interconnected network of highways and streets, we need to actually make sure that delivery is going down the right roads and finding the right town, the right house, the right mailbox," Fenton says.

With that in mind, researchers like Fenton are working on fine-tuning the lipid nanoparticles, changing their makeup, size, and charge to guide them through the body and to the right cells. Yet the challenges don't stop there. Even if you can protect the mRNA and deliver it to the right location, you also need to ensure that the mRNA can work once it gets there—and in the complex ecosystem of the human body, there are plenty of variables to deal with. So, a lot of Fenton's work also focuses on understanding how mRNA and the lipid nanoparticles operate in some of the different situations they might encounter.

In one study, for example, Fenton and his colleague Yutian Ma, a post-doctoral researcher at the Eshelman School of Pharmacy, looked at how the mRNA-lipid nanoparticle technology works in hypoxic, or low-oxygen, environments. They found that across the board, with a variety of different nanoparticles and cell types, when cells had less oxygen, they made less protein with the delivered mRNA. This is important, Fenton notes, because hypoxia shows up in a variety of diseases, including cancer, where the inside of a tumor is often a very low-oxygen environment.

Eventually, the team figured out what was causing that drop-off in protein expression. Cells with less oxygen have less ATP, or adenosine triphosphate, which the cells use as energy, and which they need to translate mRNA into proteins. So, Fenton and Ma decided to see what might happen if they entrapped ATP within the lipid nanoparticles before sending it to the cells. That worked—the team found that when they attached ATP to the lipid nanoparticles, protein expression from the mRNA was higher than it was without the ATP entrapped. And just this month, Fenton received a new $1.91 million-dollar, five-year National Institute of Health (NIH) grant from the National Institute of General Medical Sciences (NIGMS) to fund research on how lipid nanoparticles and mRNA operate in low-oxygen environments.

Fenton says he's thrilled to be doing research at UNC. "There's just so many outstanding faculty I get to work with," he says. "It's kind of funny, because I grew up reading all their papers and now, I get to be their colleague." In addition, he says the K12 program gives him a chance to interact with people outside of his own expertise, such as medical professionals who can offer clinical perspectives, along with vital mentorship and community.

"I'm always astounded by my peers," Fenton says. "They are so incredibly brilliant and collaborative and nice. And I find being around a really positive environment like that, where people are nice but also really smart, so invigorating for creativity."

And while most of the technology Fenton studies is still years away from reaching patients, some mRNA-based medicine has already had a major impact on the world—both the Moderna and Pfizer/BioNTech vaccines for COVID-19, developed in 2020, use mRNA.

"I think you always sit there thinking that 40, 50 years down the line, maybe this research will go somewhere…I flew back from Singapore in 2021 and got vaccinated and I remember thinking to myself: How cool is this?" Fenton says.

"It was this really cathartic experience for me," he adds. "These technologies that I've studied for so long are suddenly making a really big global impact. It was really—it was almost emotional, in kind of a nerdy-ish way."