RNA: Life's Exquisite Machinery by Robert Irion

UCSC Review Summer-Fall 1994

A dynamic research group at UCSC tackles one of biochemistry's most daunting challenges: understanding the many structures and functions of the extraordinary molecule called RNA.

Feeling overwhelmed by information? That's understandable, because it's everywhere. It's encoded in magnetic strips on credit cards and little black stripes on groceries. It streams down from satellites and beams nonstop from radio and TV towers. It zings through computer networks in staggering amounts. So much information bombards us that we invent fancy machines just to store it, copy it, transfer it, decode it, and express it in forms we can use.

Those machines seem like miracles of modern technology. But in fact, they are poor imitations of remarkable devices inside the cells of every living thing. For billions of years, tiny biological factories have processed the torrents of information necessary to sustain life, with a speed and precision that any assembly-line boss would envy. This machinery is powered largely by one amazing substance: RNA.

RNA, short for "ribonucleic acid," labors in the shadow of its celebrated cousin DNA. Just last year, the dinosaur-cloning scientists of Jurassic Park treated audiences to a sensational DNA tutorial. DNA deserves its fame--it is the genetic repository of our physical selves, a personal encyclopedia in every cell. But RNA, it turns out, is far more dynamic. DNA would be useless without RNA, for RNA translates DNA's instructions, ferries them out of the cell's nucleus, and converts them into the proteins our bodies need to survive. Along the way, RNA even edits itself to guarantee the accuracy of its work. RNA can play these crucial roles because of its flexibility: It twists like a tangled telephone cord into intricate and active three-dimensional forms. DNA, on the other hand, is essentially a long thread--a shape that preserves information but does little else. All of this makes biologists suspect that RNA, not DNA or protein, is life's most ancient molecule.

How does RNA perform so many tricks? That's what a burgeoning group of scientists at UCSC is trying to find out.

The group, known as the Center for the Molecular Biology of RNA, arose in 1992 with a five-year, $2.5 million grant from the Lucille P. Markey Charitable Trust. Nine faculty members and many postdoctoral researchers, graduate students, and undergraduates explore various aspects of RNA under the auspices of the center. The scientists, a mix of biologists and chemists and of young and veteran researchers, agree that these focused studies--and the prestigious Markey name--are putting UCSC on the map.

"It's already one of the best RNA centers, and our goal is to make it the best," says assistant professor of chemistry Joseph Puglisi, who came from the Massachusetts Institute of Technology to UCSC last year after being wooed by more noted schools. "The atmosphere here is excellent, and I have better facilities than I did at MIT," he says. "I know I made the right decision."

Puglisi's enthusiasm stems in no small part from the presence of Robert L. Sinsheimer Professor of Molecular Biology Harry Noller, a leading RNA expert. Noller is just the second "homegrown" UCSC scientist, after astronomer Sandra Faber, elected to the National Academy of Sciences. He directs the center with an eye toward fostering the careers of younger researchers, a rare attitude for such a prominent figure.

"Harry is extremely personable and approachable, and he's an amazing source of ideas," says associate professor of biology Manuel Ares, Jr. "He's a perfect foundation on which to build a group like this."

Noller's lab group is best known for its trailblazing work on the ribosome, an incredibly complex factory made of RNA and protein. Tens of thousands of ribosomes fleck each cell, making proteins in response to signals from the nucleus. Like synchronized machines with impeccably meshing parts, ribosomes manufacture new proteins piece by piece, forging about fifteen links per second until the protein chains are complete.

Over the last 26 years, Noller and his coworkers at UCSC have shown that RNA, not protein, drives the ribosomal machine--a notion most biologists found heretical at first. "Early in his career, Harry's contributions were not popular and didn't get much recognition," says Ares. "But then it became obvious that his approach was correct all along. You get extra respect for something like that." The coup de grace came two years ago, when Noller's group won acclaim for finding that RNA by itself can link protein pieces together, with little or no help from the rest of the ribosome.

Ultimately, Noller and other "ribocentrics" dream of a complete blueprint for the ribosome, which would represent a triumph of persistence and exacting science. But many basic details remain unknown, such as how the ribosome moves when it churns out proteins.

"Whatever you find out about ribosomes is applicable to every organism on the planet and to life in general," says Noller. "They are the common denominator of life." But the difficult research, he observes, is not for the faint of heart: "I sometimes think of the ribosome as the Omaha Beach of molecular biology, with corpses of postdocs and graduate students strewn across the beach over the decades."

Other projects at the center are similarly vexing. Ares studies "spliceosomes," fleeting clusters of RNA and protein in the nucleus. Spliceosomes take raw messages from the DNA, edit out bits that don't belong, and splice the remainders together. This yields the polished RNA message that a ribosome can read. It's yet another layer of complexity in the cell's information mill.

"Spliceosomes are Rube Goldberg RNA devices," Ares says. "They are assembled every time they function, and the assembly process is very elaborate. We are years away from understanding as much about them as we do about ribosomes."

Puglisi and professor of chemistry Thomas Schleich examine the structures of small pieces of RNA with a powerful tool called nuclear magnetic resonance (NMR) spectroscopy. NMR probes the patterns of atoms in a molecule just as a medical MRI scan probes the body's soft tissues. UCSC's state-of-the-art magnet, purchased with about $700,000 of Markey Trust funds, will help reveal the precise 3-D shapes of RNA fragments that Noller's team has modeled indirectly for years.

There is a good reason why researchers care so much about these shapes: The 3-D structure of a biological molecule is critical to determining its job in the body. Millions of tiny molecules constantly bump into each other in and around every cell. When two of them fit together, they often will react, like a key opening a lock. For example, a specific antibody in the bloodstream might attach to a knob on the surface of a foreign substance to prevent it from invading a cell. "But these molecules can subtly change their shapes to work more efficiently--the key changes shape to fit the lock better, or vice versa," says Puglisi. He suggests a more realistic metaphor: "flexible puzzle pieces."

For the pharmaceutical industry, solving those puzzles is not just child's play. One of the most exciting approaches toward creating new drugs is "rational drug design." Schleich explains: "Say you understand the 3-D structure of a molecule that carries out part of the life cycle of a virus. You then have a rational basis for designing a drug that interferes specifically with that structure but with nothing else. Disease ultimately boils down to whether molecular interactions happen or don't happen." Many of those interactions, he notes, involve RNA--including key steps in the reproduction of the viruses that cause AIDS and hepatitis. Those viruses use RNA, not DNA, to store their genetic codes.

Another goal is figuring out how existing drugs work at the molecular level, an enigma for most drugs today. Puglisi uses NMR to see how antibiotics with certain shapes can clog the gears of ribosomes in disease-causing bacteria. Some hardy bacteria, it appears, have altered the structure of their ribosomes just enough so that antibiotics no longer kill them. How this happens is a mystery.

The issue that truly has put RNA in such vogue, however, is its role in the origin of life. Not long ago, researchers studying how life began on earth faced a chicken-and-egg paradox. DNA needs protein to copy and maintain itself, but cells cannot make protein without instructions from DNA. Neither DNA nor protein, it seemed, could have come first. RNA offers a way out: It can store information, like DNA, and it can react with itself and other molecules, like protein. Although riddles remain, biologists now speak confidently of a primordial "RNA world" from which modern forms of life eventually sprang.

Traces of that world linger today. For example, some pieces of RNA in the ribosome are exactly the same in every creature on the planet, from humans to the most primitive pond scum. The implication is that any change in those precious bits of RNA would have stopped evolution dead in its tracks. "It's almost eerie," says Noller, "that after three-and-a-half billion years of evolution, organisms haven't changed at that fundamental level."

In a sense, then, RNA is a biological palimpsest: a living parchment upon which modern writing has replaced, but has not yet completely erased, the words of lost generations.

For more information about the Center for the Molecular Biology of RNA, call (408) 459-3703 or send email to king@orchid.ucsc.edu.