Reading a Book That Never Ends

Olivia Rissland explores the boundary of known and unknown

By Mark Couch

April 2022

Olivia Rissland, DPhil, compares RNA to photocopies of pages of books at a library.

“RNA is to DNA what photocopies are to precious books in library stacks: An abridged reproduction with a temporary existence,” explains Rissland, a scientist with the University of Colorado’s RNA Bioscience Initiative.

You can read just a few photocopies, and only for a limited time. Understanding those copies depends on where and when you read them. Even then, you get a just a few clues about what’s in the book; you don’t get the whole story. Those pages won’t easily yield the library’s secrets.

“What is really cool about RNA is what happens to those photocopies once they leave the library is different for each photocopy,” Rissland says.

Figuring out which photocopy to read and how to interpret what it’s saying before it disappears is a challenging task at best. It becomes a staggering enterprise when considering the numbers.

There are some 20,000 genes in the human genome. In humans, genes vary from a few hundred DNA base pairs to more than 2 million bases. Messenger RNA – the temporary photocopy – provides a picture of a piece of the DNA, a snippet of the story.

But ask Rissland about the challenge of studying those photocopies and you discover that it’s more than a practical question for framing a particular study. It’s a philosophy.

“I think about what research is,” Rissland says. “Research exists at the boundary of known and unknown. And so, what we’re always looking for are mysteries and things that don’t make sense. We are trying to understand what it is that we’re missing, that explains what we see.”

INVESTMENTS LEAD TO BOOST IN RNA RESEARCH

Rissland, an assistant professor of biochemistry and molecular genetics, joined the CU School of Medicine in 2017 when the school boosted investment into RNA research, thanks to a gift from The Anschutz Foundation and other supporters. Those funds allowed Dean John Reilly, Jr., MD, to target strategic growth opportunities, which is how the RNA Bioscience Initiative, or RBI, was born.

The goal with these investments is to bring together teams of scientists to work on some of the most challenging questions in human health.

“I think we’re very lucky in the RBI,” Rissland says. “It’s easy for us to foster collaborations. There were five of us who were hired in the same search. We’re all close enough in our work that we can have a conversation with points of common interest. But we’re not so close that there’ll be competition. For me, that is probably the starting point for all the collaborations. We are bouncing ideas with others in the offices right here and then building out from there.”

Rissland’s lab studies what happens to messenger RNA, or mRNA, after it’s made. Specifically, she and her lab team are trying to understand how the mechanics of protein production and of mRNA destruction connect with one another. Why do some mRNAs get destroyed quickly and others slowly?

The processes are connected, but how remains a multifaceted mystery – and a source of endless fascination for Rissland and the team of scientists in her laboratory. Understanding what happens during that interaction could yield insights into genetic factors causing of human disease.

Although all cells have the same collection of genes, cells differ in which genes are turned on and which are turned off. When that process goes awry, adverse health conditions can result, such as cancer, neurodegeneration, or developmental defects.

One area of inquiry for Rissland’s lab is the impact of “translation elongation speeds” on how fast mRNAs are destroyed. Translation occurs when the ribosome in the cell “reads” the sequence on the mRNA and turns that into a sequence of amino acids, thus building proteins.

“You have these machines – they’re called ribosomes – that are the actual interpreters that go between the different languages and make the protein,” Rissland says. “The speed at which the ribosome moves matters. A way to think about this is like on a freeway.”

You accelerate as you get on the freeway, but your speed can vary once you’re on the road. That time span between destinations is “elongation.” Your speed depends on weather, it depends on traffic, and sometimes you slow down or speed up depending on the conditions. In a cell, a traffic jam is a signal that there’s a problem, “that there’s something a little bit wrong about the RNA, then the cell takes action to deal with that,” Rissland says.

There are ample opportunities for traffic jams in a cell because the average cell produces 2 million protein molecules every minute. For a researcher, that means there are ample opportunities to explore.

“That’s when you sit down and try to come up with what question to ask,” she says. “You read the literature and you say, ‘Well, what things are here that don’t make sense? What things surprise me? Or what is an implication of something that we know if this is true, then that would imply this is true?’”

Questions shape the experiments, and the experiments provide answers.

“The majority of the time it doesn’t work the way you think it’s going to,” Rissland says. “You think it could be answer A or it could be answer B. And it’s always answer C.”

CHARTING A NEW PATH

Surprise endings are nothing new in literature or life.

Rissland had planned to go to medical school after completing her undergraduate degree in Biology, Mathematics, and Classics (Latin) at Brown University in 2004. She was awarded a Rhodes Scholarship and went to University of Oxford where she earned a DPhil in molecular biology.

“The plan actually was to come back to the States and go do my MD,” Rissland says. “Then I’d be an MD, PhD, and drive off into the sunset.”

Well, plans change, and the sun also rises. In Rissland’s case, the light on the horizon was the opportunity to become an independent investigator running a research laboratory.

“When I came of age as a scientist was right when we started having all of these methods that allow us to ask questions about RNA and answer them. Five or 10 years earlier, this just wasn’t possible,” Rissland says. “For me it was not only that there were all these questions that I wanted to answer, but we also had these tools to answer them. It was just this huge technological revolution. I mean, it’s like being a kid in a candy store. How could you say no to that?”

The advent of high-throughput sequencing technology has allowed scientists to look widely and deeply into the full spectrum of genetic variations and other factors affecting biological change that were impossibly laborious to study for previous generations of investigators.

“Classically, we were able to look at gene A or gene B and we looked at them one by one,” she says. “What high-throughput sequencing allowed us to do is to not look at things one-by-one, but to look at every single gene at the same time and that gives you just so much more power.”

It’s the power to think about the themes and larger plot of the story rather than paying attention to one or two characters in a book.

“I am most interested in general principles,” Rissland says. “Specific examples don’t provide general insight. They are fine, but they’re not what really get me out of bed in the morning. And to know if something is general you need to be able to look at many things. High throughput sequencing, then, is a really good match for the types of questions I like to ask.”

After completing her doctorate, Rissland did postdoctoral work at the Whitehead Institute, an independent biomedical research institute in Cambridge, Mass., and then launched her laboratory at The Hospital for Sick Children, which is affiliated with the University of Toronto, in 2014.

Since starting her career as an independent investigator, her laboratory has trained more than 20 young scientists, nurturing their research, preparing them for their own careers, and encouraging them to ask questions.

“I think success looks like someone who has taken real intellectual ownership of their project, who pushes back against my ideas, who tells me that I’m wrong. I think when they do that, that’s the best part. It means that they have the skills so that they can put those ideas into practice.”

It’s like reading a book that never ends.