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Splice of life

When the Human Genome Project announced its findings in 2003, the surprise was how few genes we humans have—30,000 or so—to control the production of the 100,000-plus bodily proteins that keep us ticking.

How do we do it? By chemically cutting and pasting portions of genetic code to create new permutations. How that processing works—and works correctly—inside the cell’s nucleus is a hot new topic in biology. And it’s the specialty of Pat Hilleren, Skidmore’s Lubin Family Professor for Women in Science. As a researcher in the Howard Hughes Medical Institute at the University of Arizona, she co-authored a 2001 article in Nature, a top science journal, and now she’s won a five-year, $720,000 grant from the National Institutes of Health to delve deeper.

Hilleren explains it all with gusto, clear language, and liberal use of a whiteboard. A simple précis goes like this: Protein-making instructions are encoded in the genes’ DNA. Gene expression—that is, the delivery and carrying out of the instructions—begins with an RNA copy of the code, called “pre-messenger RNA.” Picture the pre-mRNA as a train: boxcar-like bits of code, called exons, are separated by linkages, called introns. In RNA processing, introns are chemically spliced out so that the exons on either side join contiguously to create new code sequences.

The splicing is done by a tiny body of chemicals known as a spliceosome, which binds onto an intron, cuts it out, and then moves on to its next splicing task. Or sometimes not: If an intron is flawed or the chemistry goes awry, the spliceosome may get stalled or stuck. Not only does the splice fail, but the stuck spliceosome can’t continue its appointed rounds elsewhere, and the faulty intron stays hidden from the enzymes that should rid the cell of such bad rubbish. Soon, says Hilleren, “it’s like a traffic jam. Wrecked cars clog the road, and the tow trucks are blocked in too. It could shut down gene expression, and the cell could die.” Given the zillions of splicing operations occurring in cells all the time, such errors are not infrequent; yet most cells function well. Evidently, then, some kind of quality-control system must be unsticking stuck spliceosomes.

(“Are you still with me?” Hilleren asks, pausing for breath. “Great. This is fun!”)

In the lab Hilleren studies this “RNA quality control” in a common yeast. It shares essentially the same biological processing as human cells, but, she adds, “it’s easier to bust open the cell and manipulate individual genes.” First she chemically infuses into the yeast cell a “reporter gene” (so called because it can be uniquely traced and recognized), which she’s engineered so that its RNA copies will include a deliberately botched intron. Then she watches nature take its course: As these RNAs with bad introns are being spliced, do they accumulate, indicating stalled spliceosomes? or do their levels drop, indicating efficient disassembly and cleanup? (In fact, what she watches are only indirect indicators: After painstaking, high-tech chemical processing, the concentrations of reporter-gene components can be imaged as a series of gray bands on a white card.) By varying the introduced introns or other factors, and comparing the results over many tests and controls, Hilleren aims to pinpoint the agents and mechanisms of spliceosome disassembly.

This kind of lab work takes patience, careful planning of the how-to and the what-next, and faith in the probes and procedures that give a visible reflection of the results. “The research is very analytical and long-term, but it’s incredibly satisfying,” notes Hilleren. At the same time, she says, “the other side of my personality loves teaching, where the rewards can be same-day and lots of fun. I like the mix; they feed each other in good ways.” —SR