Melissa Moore can get excited by just about any kind of science, and she's an avid believer in the role that serendipity, combined with good advice, plays in determining one's career.
Moore initially became interested in enzymes, the tiny biochemical machines that catalyze all chemical reactions inside cells, during her undergraduate thesis work. When it came time to go to graduate school, she only applied to one place—the Massachusetts Institute of Technology—because she couldn't afford multiple application fees. There she worked under Christopher Walsh, a well-known enzymologist, on bacterial enzymes that detoxify mercury. When it came time to choose a postdoctoral lab, Walsh suggested that she consider Phillip Sharp, also at MIT. That decision set her on a path to a series of discoveries about how RNA is processed and used by cells.
"I never started out to work on RNA, but that's where I've happily ended up," says Moore. "Sometimes when students talk to me, they seem to think they need to have their entire future planned out from the start. But they don't. I certainly didn't."
Sharp, who shared the 1993 Nobel Prize in Physiology or Medicine with Richard Roberts, had discovered that genes aren't coded in an unbroken string of genetic letters. That is, the DNA that spells out genes isn't contiguous, but rather it is divided up into coding segments and noncoding segments. Cellular machinery reads the appropriate segments and splices together RNA, which makes a recipe for a protein. Sharp invited Moore into his laboratory, but only if she agreed to work on the RNA-splicing machinery, called the spliceosome.
"When I started working on RNA, I just fell in love with it," says Moore. She liked the simplicity of the rules of RNA. Because of base pairing, it's easy to predict how RNA molecules will interact with each other. "Since then, everything I've done has centered on RNA."
Moore has spent much of her time since dissecting the spliceosome—a giant molecular machine whose role is essential in human biology. The human genome is relatively small, carrying about 25,000 genes. That's not many more than a fly has. But most human genes are alternatively spliced, meaning they code for more than one protein. That way, the whole panoply of human proteins gets squeezed into a relatively compact genome. It's efficient, and the spliceosome makes this possible. A complex of many proteins, the spliceosome latches onto RNA as it unspools off of the nuclear genome, then it stitches the proper genetic segments together into a protein-making code. In short, the spliceosome is a molecular marvel that Moore is helping unravel.
"It's a much more complicated machine," Moore says of the spliceosome, comparing it to the better known ribosome, which makes proteins from RNA. "It has five major parts, and they're very dynamic in how they move and interact with RNA, how they come and go."
One of Moore's major discoveries to date is a passel of proteins called the exon junction complex (EJC) that helps control the translation of messenger RNA into protein. The EJC gets plopped onto RNA splice sites in the nucleus, providing a "nuclear history" as the RNA moves into the cytoplasm of the cell. There, the EJC helps direct the RNA to the correct location in the cell, where it impacts how efficiently RNA is translated into protein and whether the RNA should be deposited into the cellular trash bin.
"When messenger RNA leaves the nucleus, it leaves not just as naked RNA but as RNA complexed to many proteins," says Moore. "I call this 'nuclear nurturing' and it affects what happens to the RNA downstream."
Moore also takes pride in inventing her own tools, which she then shares with the scientific community. Recently, her laboratory has been developing methods to watch individual spliceosomes assemble and splice RNAs in real time. The techniques they are creating, in collaboration with Jeff Gelles at Brandeis University, should be applicable to many other complicated biological systems. "I find tremendous satisfaction in developing techniques that are useful to the whole field," she says.
Moore is now moving beyond the spliceosome to probe deeper mysteries of RNA and RNA as a disease-causing agent or therapeutic target. One evolving interest concerns the potential roles of damaged RNAs in neurodegenerative diseases such as amyotrophic lateral sclerosis. She also recently discovered a small molecule that inhibits the spliceosome. This molecule has hinted that it might have anticancer potential, too. "Inhibitors of splicing may be novel anticancer agents," she says. "This is not a therapeutic avenue that has been previously exploited."
