Upending the Conventional Wisdom About RNA

In Shakespeare’s plays, messengers are among the most important characters, appearing on stage at critical moments to deliver news that dramatically influences how the tale unfolds.

In biology, similar recurring “characters”—messenger RNAs (mRNAs)—appear within our cells. The role of mRNA is to deliver information encoded in our DNA to the cell body, where the information is translated into proteins that carry out nearly every task of life. In other words, mRNAs make sure our genome’s story is told.

The actors who play Shakepeare’s messengers aren’t stars, and, until recently, the processes that control mRNA weren’t paid much attention either. It was believed that the quantity of mRNA dictated the quantity of protein produced.

But in recent years, biologists have come to appreciate that something else is going on with mRNA that can dramatically affect how much of a given protein is made, with its attendant impacts on cell function.

That has researchers like Sara Zaccara, PhD, assistant professor of systems biology, asking “What regulates these vital messengers?”

The answers are helping biologists understand how cells adapt to changes in their environment and how control of mRNA contributes to disease and could open a rich trove of new therapeutics.

A world beyond Lauria

Zaccara’s unlikely journey to Columbia began in Lauria, a small medieval town in the hills of southern Italy. Ever curious, Zaccara loved learning about philosophy and history before gravitating to science and a career in research. Her parents were skeptical, worried that the long years of training wouldn’t pay off. “Why not become a doctor?” they implored, a job with a more secure future and defined training path that didn’t involve living so far from home.

Zaccara persisted, even though it meant venturing far from home, first for training in Florence, then in London, Trento (Italy), Colorado, and Manhattan. Along the way, she began to focus on p53, the well-known tumor suppressor protein. While most researchers studied how p53 controls the transcription of other genes, she looked at what might happen to these genes at the post-transcriptional and translational levels. “It seemed that there’s regulation of p53-target protein abundance even after the mRNA is produced and it wasn’t well explored,” she explains.

As a postdoc, she decided to concentrate on this new area of post-transcriptional regulation, which would become known as epitranscriptomics (“epi” meaning “following” or “subsequent to”).

“It was a bit risky,” she admits. “It was a new field, full of unknowns and contradictions, and it might not lead anywhere. But I liked the challenge."

Making a mark in epitranscriptomics

In 2016, after she finished graduate school in Italy, she reached out to Samie Jaffrey at Weill Cornell Medicine, one of the founding fathers of epitranscriptomics (a term he coined). Jaffrey welcomed her aboard as a postdoc, beginning a fruitful collaboration.

During her time on the east side of Manhattan, Zaccara became intrigued by m⁶A, the most abundant and perhaps most significant of the hundreds of mRNA modifications that regulate mRNA activity. m⁶A modifications—when a methyl group attaches to the N-6^th position of an adenosine within the mRNA transcript—were first discovered in the 70s, but little was known about their abundance or functions until the early 2010s.

One of her discoveries, published in Cell in 2020, has already upended a prevailing model of how m⁶A exerts its effects and has important ramifications for how targeting m⁶A could influence the course of disease. In that paper, Zaccara showed that YTHDF proteins—which mediate how m⁶A affects mRNA degradation—work together, not independently, as was previously thought.

Her studies also demonstrated that elevated m⁶A levels contribute to the development of acute myeloid leukemia, suggesting that drugs that target m⁶A may prove useful in treating this and, perhaps, other cancers. One of these drugs is now in an early phase 1 trial for AML.

Daring science and creative baking

Zaccara’s daring has clearly paid off. Epitranscriptomics is no longer considered an obscure outpost of cell biology, “although I still have to explain what I do to some colleagues,” she says. Her parents are now very proud and supportive of her choice.

Last year, Zaccara joined the Columbia faculty, finding a large group of like-minded scientists in the Department of Systems Biology. “I fell in love with the philosophy behind the department, with experts in so many different fields sharing the same ‘systems’ approach to understanding biological complexity,” she says.

By any measure, she’s had a productive year: being named one of StatNews’ Wunderkinds of 2022, winning a grant from the National Institutes of Health to expand her studies of YTHDF proteins; co-organizing the first NYC RNA Symposium, bringing together most of the NYC area’s experts in the RNA field with over 250 participants; and winning, alongside her lab partners, the 2023 Columbia RNA Day Cake Competition with a lemon cake colorfully decorated with RNA modifications.

A long way from home, Zaccara misses her family and having mountains outside her back door. But she’s also learned to love New York City. “You can make a big city a small city by finding your favorite shops, making your own community,” she says.