How Catalytic RNA Redefined Enzymes and the Origin of Life

There have been many important discoveries along the path to what we know today about RNA, or ribonucleic acid-a molecule found in every living cell that helps carry and interpret genetic instructions.

In 1868, Swiss physician Friedrich Miescher first identified nucleic acids. In 1956, Alex Rich and David Davies, both researchers at the National Institute of Mental Health, hybridized two separate strands of RNA to form the first RNA crystal, revealing that RNA could form stable, structured molecules-not just transient messengers.

Then, in 1989, Sidney Altman of Yale School of Medicine and Thomas Cech of the University of Colorado Boulder won the Nobel Prize in Chemistry for discovering that RNA itself had catalytic properties-the ability to accelerate chemical reactions inside cells. RNA was not just carrying instructions. It was performing the chemistry of life.

At the time, the Nobel committee characterized the discovery, alongside the discovery of DNAs double helix structure, as one of "the two most important and outstanding discoveries in the biological sciences in the past 40 years."

Altman's research opened entirely new fields of research and reshaped how scientists understand biology, laying the groundwork for advances that continue to shape science today.

Rethinking RNA: The Discovery of Ribozymes

Before Altman's discovery, scientists believed that enzymes-biological catalysts that speed up chemical reactions-were made exclusively of proteins. RNA was considered a passive courier, ferrying genetic instructions from DNA to the cellular machinery that builds proteins.

Altman's research challenged that assumption. While studying how cells process transfer RNA (tRNA), Altman investigated an enzyme called RNase P, which contains both protein and RNA components. Scientists assumed the protein was responsible for its activity.

Altman removed the protein. To his surprise, the RNA component continued to function independently. It could catalyze the reaction on its own. This demonstrated that RNA can act as an enzyme-a catalytic RNA molecule now known as a ribozyme.

At the time, the idea that anything other than proteins could catalyze chemical reactions was considered implausible. Altman faced skepticism from peers and pushback from the scientific establishment. Around the same time, however, Thomas Cech independently discovered self-splicing RNA molecules, confirming that catalytic RNA was not an isolated anomaly.

The implications were profound. As the Nobel press release stated, "Many chapters in our textbooks have to be revised."

From Ribozymes to CRISPR and RNA Medicine

Altman's discovery fundamentally changed how scientists think about RNA. His work helped establish RNA as a versatile and functional molecule-a conceptual shift that underpins many of today's most important biological technologies:

Messenger RNA (mRNA) vaccines, such as those developed during the COVID-19 pandemic, rely on RNA's ability to deliver genetic instructions safely into cells.

RNA-based therapeutics are being developed to treat genetic diseases, cancer, and viral infections.

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), a gene editing tool that uses RNA molecules to guide precise changes in DNA.

"Sid's contribution to the field of RNA biology was massive and came at a time when most researchers looked past RNA as just a chemical variation of DNA," says Ronald Breaker, PhD, Sterling Professor of Molecular, Cellular and Developmental Biology at Yale School of Medicine. "His discovery of an RNA that worked as a true enzyme revolutionized the way the entire scientific community thought about enzymes and about the origin of life. His research influence is felt in every research project we pursue."

RNA and the Origin of Life

Altman's discovery also reshaped theories about life's beginnings.

For decades, scientists struggled with a paradox: proteins are required to catalyze chemical reactions, but proteins themselves must be built from genetic instructions stored in DNA or RNA. Which came first?

If RNA can both store information and catalyze reactions, it offers a compelling solution. This idea-known as the "RNA world" hypothesis-proposes that early life may have relied primarily on RNA before DNA and proteins evolved into their current roles.

Altman did not invent the RNA world theory, but his work provided powerful evidence that made it scientifically plausible.

A Life in Science and Service

Altman joined the Yale faculty in the 1970s and spent decades building a world-class research program in RNA biology. He was a prolific mentor and champion for funding young scientists with big ideas, and served as dean of Yale College from 1985 to 1989. He worked to ensure that science majors gained an appreciation of the arts and humanities and, reciprocally, that non-scientists would recognize the value of science.

Altman died in 2022 at age 82.

Today's RNA Revolution at Yale

Altman's discovery did more than rewrite textbooks-it helped establish Yale as a global center for RNA biology. That legacy continues through the Yale Center for RNA Science and Medicine, which brings together researchers across disciplines to study how RNA structure governs function and how RNA-based mechanisms can be harnessed to treat disease.

Today, investigators at Yale are exploring how RNA folds into intricate three-dimensional shapes, how it regulates gene expression, and how disruptions in RNA processing contribute to cancer, neurological disorders, and viral infection. They are also advancing RNA-targeted therapies, refining CRISPR-based technologies, and developing RNA-editing tools that aim to correct genetic errors without permanently altering DNA.

From catalytic ribozymes to programmable molecular tools, the exploration that began in Altman's laboratory continues to expand RNA's potential. At Yale, it remains a frontier.