In 1957, just four years after Francis Crick and other scientists solved the riddle of DNA’s structure—the now famous double helix—Crick laid out what he called the “central dogma” of molecular biology, which his colleague James Watson later said implied that biological information flows inexorably from DNA to RNA to proteins. Although Watson was oversimplifying, the message was that the purpose of the double helix in our chromosomes is to hold, in encoded form, blueprints for the proteins that build and maintain our bodies. DNA’s chemical cousin, RNA, was the messenger that carries DNA instructions from the double helix in the cell’s nucleus to the protein-making machinery, called the ribosome, scattered around the cell.
Molecular biology’s mission, it seemed, was to decipher those genetic instructions. But in recent years researchers have discovered a dizzying array of “noncoding” RNA (ncRNA) molecules that do something other than ferry DNA instructions for proteins. They perform a surprisingly wide range of biochemical functions. It now seems that our genome may be at least as much a repository of plans for vital, noncoding RNA as it is for proteins. This shift in thinking has been “revolutionary,” says Thomas Cech, who shared the 1989 Nobel Prize in Chemistry with Sidney Altman for discovering RNA molecules, called ribozymes, that can catalyze biochemical reactions. “DNA is old stuff, 20th-century stuff,” Cech says. “It’s a one-trick pony. All it does is store biological information, which it does exquisitely well. But it’s inert—it can’t do anything without its children, RNA and proteins.”
RNA is created when an enzyme called RNA polymerase reads a DNA sequence and builds a corresponding RNA molecule—a process known as transcription. The discovery, over the past three decades, of thousands of previously unknown noncoding RNAs “has been mind-blowing,” says Maite Huarte, a molecular biologist at the University of Navarra in Pamplona, Spain. Noncoding RNA plays many roles, often involving the regulation of other genes—for example, determining whether protein-coding genes get transcribed to messenger RNA (mRNA) and how (or if) that molecule is edited and then translated into a protein. In this case, RNA seems to control how cells use their DNA. These functions turn the popular central dogma, which was a one-way street from DNA to mRNA to proteins, into an open system with information flowing in all directions among DNA, proteins, cells and organism.
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Equally fascinating, Huarte says, is that ncRNAs don’t belong to just one family of molecules. “RNA is highly versatile, and nature exploits this versatility,” she says. Scientists have known since the 1950s that ribosomes contain ribosomal RNA and use transfer RNA to collect amino acids that are stitched together in proteins. But for a long time those seemed like anomalies. Then, in the 1980s, Cech and Altman discovered a new type of ncRNA: ribozymes that cleave and edit themselves and other RNAs. And in the 1990s researchers began to find human ncRNAs that had regulatory functions. A gene called XIST, involved in the “silencing” of one of the two X chromosomes in the cells of chromosomal females, encoded not a protein but a long noncoding RNA that appears to wrap around the chromosome and prevent its transcription.
“Textbooks 25 years ago confidently stated that RNA consisted of [three types]. Now there are hundreds, likely many thousands, of other types.” —Thomas Cech University of Colorado Boulder
Meanwhile molecular biologists Victor Ambros and Gary Ruvkun found short noncoding RNA molecules that interact with mRNA to silence a corresponding gene. This extra layer of gene regulation—controlling whether an mRNA is used to make a protein—seems to be an essential feature in the growth of complex organisms. Scientists have linked genetic mutations that hinder gene regulation by ncRNAs to a wide range of diseases, including cancers. “We’re getting closer to some really exciting biomedical applications,” Huarte says. “From new diagnostic tools to innovative, targeted therapies, the potential of ncRNAs is huge.”
Cech says it was a “big surprise” RNA could perform such diverse roles. That surprise was apparent in 2012 when scientists working on an international project called ENCODE reported that as much as 80 percent of our DNA has biochemical function in some cells at some point, and much of that DNA is transcribed into RNA, challenging the long-held belief that most of our genome is “junk” accumulated over the course of evolution.
This is not a consensus view. Some researchers argue that, on the contrary, most of the RNA transcribed from DNA but not translated into protein is “noise,” made because the transcription machinery is rather indiscriminate. Such noise will indeed be the end result for some transcription. It now appears that known noncoding genes outnumber genes encoding proteins by a factor of about three, according to some estimates.
It’s often hard, however, to figure out just what the RNA is doing. Some of these molecules might get transcribed only in particular types of cells or at a particular stage in embryonic development, so it would be easy to miss their moment of action. “They are incredibly cell-type specific,” says molecular biologist Susan Carpenter of the University of California, Santa Cruz. But because of that, she says, “the more we look, the more we find.”
Ambiguities notwithstanding, the rise of RNA has transformed molecular biology. “Textbooks 25 years ago confidently stated that RNA consisted of messenger RNA, transfer RNA and ribosomal RNA,” Cech says. “Now there are hundreds, likely many thousands, of other types.” The 21st century, he says, “is the age of noncoding RNA.”
We have much more to learn. We don’t know how much functional ncRNA there is, let alone what the many varieties do. And “when we answer one question, it raises 10 new ones,” Carpenter says. As scientists discover more about the many types and roles of RNA, medical researchers may discover potential therapeutic applications, yet the more profound implications are about how life works. For complex organisms to be viable, it’s simply not enough to have a “genetic blueprint” that gets read. They need to be able to change, on the fly, how their genes get used. RNA seems to offer incredibly responsive and versatile ways of doing that.
