Q&A with Brown biochemist on RNA, the molecule causing global excitement among scientists

PROVIDENCE, R.I. [Brown University] - RNA hit prime time during the COVID-19 pandemic, when the average American waiting in line for their shot knew that the vaccines from Pfizer-BioNTech and Moderna were made using mRNA. But while RNA has since become a part of the vernacular, ribonucleic acid remains extraordinarily complex, even for the scientists who study it.

The varied and extensive functions of RNA remain "the biggest black box of all molecular medicine," according to Juan Alfonzo, a Brown University professor of molecular biology, cell biology and biochemistry and executive director of the new Brown RNA Center in the Division of Biology and Medicine that launched last year. The center is focused on making basic RNA discoveries and translating their impact to patient outcomes. The center has also been catalyzing an international effort to identify and sequence all human RNA - a project known as the Human RNome Project.

Alfonzo said that the study of RNA requires the expertise of researchers from a variety of backgrounds, including biochemistry, genetics, cellular biology and more. It also requires a sense of curiosity and awe, and the same delight that Alfonzo finds in RNA research. When he describes the activity of the RNA Center, Alfonzo often uses an unexpected word: play. He talks about scientists "playing around" with nanoparticles to learn how best to deliver RNA to therapeutic targets; he uses the phrase "playing games" to refer to the process of sequencing the RNA of people and pathogens and determining how to use them to create cures and immunity. And he describes the RNA Center as a hub that convenes leading researchers from different scientific fields and allows them to test hypotheses and work out solutions together.

"To make a proper center, you get a lot of people who have diverse interests and want to focus on RNA science and who like to play well with others, and you put them together," Alfonzo said. "And then the sky's the limit."

Here, Alfonzo untangles the challenges of RNA research and explains what the Brown RNA Center is doing to maximize the molecule's potential.

Q: How is RNA different from DNA?

Ribonucleic acid used to be considered the forgotten cousin of DNA. Like DNA, RNA is present in all living cells, but structurally, it generally has one strand instead of two. All of the DNA in a cell, which collectively is known as the genome, encodes hundreds of thousands of millions of RNA molecules made from DNA, and each RNA has a different function and specific sequence of information. DNA stores information needed to make cells. But the information can't be used unless there's a way to extract it and put it into a functional entity. RNA is what delivers the DNA information to machinery in the cell that makes proteins.You can think of it like this: DNA is like a hard drive, and all of the RNA in a cell are like apps or computer programs - they take the information stored in the hard drive, process it and deliver it to where it needs to be so a cell can become a certain type of cell. Without the RNA, you can't make proteins, which means you can't make cells, or organisms or humans.

Q: How has our understanding of RNA function changed over the past few years?

Recently developed sequencing technology allows us to take a tissue sample from a biopsy and sequence, or map, a person's entire genome in a single day. But that information has to be interpreted, and the interpretation is the RNA. So the focus shifted to sequencing the RNA. Doing that led to the realization that in a genome that encodes so much RNA, only 2% is there to make proteins. What is all this RNA doing if not making proteins, then? That is probably the biggest black box in molecular biology. The Human RNome Project, which Brown is catalyzing, aims to identify and quantify all RNAs and map their modifications, in both normal and diseased human cells and tissues. But we also need to figure out function. And that takes time and that involves many aspects of science, from biochemistry to genetics to cellular biology and more.

Q: Many of us became familiar with RNA because of the development of the COVID-19 vaccine. How was that created and what does it tell us about what RNA can do?

Many years ago, scientists Dr. Drew Weissman and Katalin Karikó started asking: If typical vaccines involve proteins from viruses, is there a different way to make vaccines that don't involve injecting people with the protein itself, but with the molecule that programs the protein to induce immunity against the virus - the messenger RNA itself? There were practical challenges: RNA is fragile and can also induce a bad inflammatory response. So making a safe, effective vaccine involved not only mastering the immunity-causing mechanism but creating a way to help the RNA last in the cell without causing dangerous inflammation. During the pandemic, the modification that went into this RNA representing the COVID genome worked. And that's the understanding that won Weissman and Karikó a Nobel Prize last year. Compared to making a protein-based vaccine, which can take many months or even years, it takes no time at all to modify RNA in the lab. The beauty of RNA is that it's sufficiently stable to help solve a problem or create a cure or a vaccine, but also sufficiently unstable that it doesn't alter a person's genetic makeup, as would happen with manipulations of DNA.

Q: What do you see as some of the most exciting potential applications of RNA for health and medicine?

Sequencing all of human RNA and its modifications could help produce new diagnostic tools to detect diseases such as Alzheimer's, revolutionize understanding of the human body and lead to cures and treatments for illnesses such as cancer. But beyond health and medicine, RNA modifications also show promise for solving other challenges facing humanity, such as addressing starvation by enhancing agricultural productivity.

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