Think of DNA as the cookbook for life. From this genomic text, everything biological unspools. DNA encodes RNA, RNA encodes proteins and presto, your body builds itself and functions. 

This process, known as the central dogma of molecular biology, is far from perfect. Damaged DNA can cause breakdowns, leading to mutations and the development of genetic diseases.

Peter Beal, professor and chair of the Department of Chemistry at the College of Letters and Science at UC Davis, has long been interested in how organic chemistry can be harnessed to influence biology and health. 

For close to 30 years, Beal and his colleagues have investigated the intricacies and nuances of RNA editing, a natural process that temporarily alters RNA so it can produce the hundreds of thousands of distinct proteins necessary for the body to function.   

“We have enzymes that are capable of binding to messenger RNA and actually change the structure of a nucleotide in the messenger RNA,” said Beal, who noted that some nucleotide changes are hallmarks of genetic diseases. “What’s happened recently, and has gotten a lot of people super excited, is that we can actually direct these natural enzymes to make edits in the messenger RNA that would be therapeutically beneficial.”  

This foundational science has shown great promise. The National Institutes of Health has invested millions of dollars in the research, and Beal and his colleagues are partnering with industry to bring these RNA-based therapies to commercial market. Recently, ProQR Therapeutics, a biotech company based in the Netherlands that Beal’s team works closely with, reported positive results from a Phase 1 study that used RNA-based editing to reduce toxic bile acid accumulation in the liver, an underlying driver of cholestatic liver diseases.      

“That chemical modification that was first developed here at UC Davis is in the lead molecules that are in clinical trials directed by the ProQR team,” Beal said. “We are developing molecules that can actually direct these editing enzymes to make what you might think of as a repair.” 

What is RNA editing? 

When describing RNA editing, Beal likened it to a familial cookbook passed down through generations, an analogy first made by one of Beal’s graduate students. The cookbook is like the genome, its recipes like the complete set of an organism’s DNA.

“Imagine your grandma’s cookbook and it’s got your favorite recipe for cookies but there’s a mistake in the recipe,” Beal said. “Instead of using two eggs, it says use 20 eggs.” 

Rather than change your grandma’s cookbook, a precious heirloom, you write the recipe down on a piece of paper, correcting the 20 eggs to two eggs. That piece of paper is like the messenger RNA. It has the instructions to make the cookies, or, in the case, the proteins. 

“All the information that’s in the cookbook is like your genes and your genome, and that piece of paper that goes into the kitchen is your messenger RNA,” Beal said. 

“That’s temporary, that’s transient and that’s kind of like messenger RNA,” he added. 

This differs from gene editing tools like CRISPR-Cas9, which alters the sequence of genes at the DNA level. 

“It’s safer to change the information on the piece of paper, or at the RNA level, instead of going back and changing grandma’s cookbook, or the genome,” Beal said. “RNA editing doesn’t permanently alter DNA.”

In the body’s natural system, RNA editing is accomplished via enzymes called adenosine deaminase acting on RNA, or ADAR. These enzymes have been the primary research focus of Beal and his colleagues for the past few decades.   

How do you solve a molecular structure?

To understand ADAR enzymes at the structural level, Beal partnered with Andrew Fisher, a UC Davis professor with joint appointments in the Department of Chemistry and the Department of Molecular and Cellular Biology.

Fisher is an imaging specialist. By using techniques such as x-ray crystallography and cryogenic electron microscopy, he can glimpse in fine detail the inner structures of macromolecules, such as ADAR enzymes.

“Growing up, I always loved to take things apart, see how they work and put them back together,” said Fisher, noting his mother called him a “fix-it person.” “It’s the same thing with biology. How does a protein work? Well, let’s take it apart and look at where the individual atoms are and see how things function.”   

Fisher and his lab are analyzing ADAR enzymes and mutants from various organisms, investigating their structure to learn about their function. The team wanted to figure out how they could leverage ADAR structures to optimize their editing and repair capabilities, specifically in the context of genetic diseases. 

“The structures are helping us not only understand the mechanism but also how we can modify the RNA molecules to increase the stability inside the cell,” Fisher said. “Once we know the structure, we can see what positions of our RNA molecules may be able to tolerate modifications and not impact its interaction with the ADAR enzyme.”  

Through meticulous work, Fisher and colleagues successfully solved the crystal structure of the ADAR enzyme as it was positioned on the RNA substrate. Essentially, they developed a high-resolution molecular picture of the ADAR machinery as it interacted with RNA. 

With the structure illuminated, Beal’s team began investigating how to optimize the chemistry and make these interactions stronger. 

How do researchers make RNA editing more efficient? 

Following the determination of the ADAR-RNA substrate crystal structure, Erin Doherty, then a graduate student in Beal’s lab, started probing the individual connection points between the ADAR enzyme and the RNA substrate. 

Doherty and her colleagues noticed that when they increased the acidity of the environment, the ADAR reaction became faster and more efficient. 

“You would think that if this enzyme is optimized to work in the human body, then it’s going to work best at the neutral pH of the human body,” said Doherty, who will join Columbia University as an assistant professor in the Department of Biological Sciences in January 2027. “But when it gets more acidic, this thing works a little bit better.” 

“That was a clue that there was something there that could be optimized,” she added. 

And optimize they did. The team successfully made a molecular tweak that enabled the ADAR-RNA substrate platform to perform as it would in an increased acidity environment.

“We make this chemical modification to the guide RNA to mimic those acidic conditions and that led to an increase in the efficiency of editing,” Doherty said. “That has gone on to be part of the lead compounds at ProQR.” 

From foundational science to application

Beal, Fisher and Doherty all relish the curiosity-driven approach to foundational science. Exploring the chemical fundamentals of life for knowledge’s sake motivates their work. 

That said, it’s heartening for them to see their foundational research find its way to application. 

“That’s the best type of project, one where you’re answering a biological question that’s interesting, but then it also allows us to design something that could be important, and has proved to be important, therapeutically,” Doherty said. “What we want to do is take this basic science that really can only be done in academia and capitalize on it to better serve humanity.”

As industry continues to use their foundational ADAR research to develop next-generation therapeutics, Beal and Fisher continue to develop finer understandings of ADAR enzymes across the tree of life. Perhaps the pathway to increasing performance and efficiency lies in the genome of another species. 

“I tell my students, ‘The work you all are doing is making an impact right now,’” Fisher said. 

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