Two Careers in RNAi

A career in RNA interference (RNAi) is a true work in progress. The field is so new that virtually no one now working in it did graduate work in RNAi.

Peggy Taylor, now vice president of research for Sequitur, took a natural path, starting out with antisense work while in graduate school at Harvard University. Her work focused on a particular flavor of antisense called morpholino, which blocks the ribosomal machinery rather than causing digestion of target messenger RNA.

After a postdoc at the Harvard School of Public Health, Taylor's antisense experience helped her join Sequitur in 1998, where she used antisense for target identification. When researchers at the Max Planck Institute for Biophysical Chemistry demonstrated in 2001 that RNAi could function in mammalian cells, Sequitur began to switch to the new technology. Within 6 months, they had made a nearly complete transition, Taylor recalls.

The rapid switch parallels the stunning speed with which the biotechnology community has adapted the new technology. "Our expertise in the cell systems and transfection protocols really helped make it a smooth transition," she says. That is undoubtedly part of the appeal of RNAi--it requires no new equipment or expensive, unfamiliar reagents, so researchers have rapidly adopted it.

Although some have hailed RNAi as more specific in its gene targeting than antisense, Taylor says that the biggest benefit came from RNAi's innocuous nature. Antisense causes a nonspecific interferon response that typically causes cells to begin to die within 3 or 4 days of the first transfection. RNAi showed no such toxicity. "In cases where we didn't see full inhibition, we were able to increase the dose we were giving to cells because we weren't running up against the toxicity barrier," Taylor says. RNAi's longer-lasting effect was also a plus, allowing analysis of endpoints up to 4 or 5 days after the initial transfection.

Although she entered the RNAi field more recently, Tracy Zimmermann took a more circuitous route than Taylor. Her graduate work at the University of Colorado focused on the mechanistic details of a catalytic RNA. For her postdoc, she studied the mechanism of ribosomal subunit assembly and export in yeast at Harvard Medical School, and from there she joined the pharmacogenomics company Variagenics Inc. in Cambridge, Massachusetts, (now part of San Francisco-based Nuvelo). There she worked on genotyping and DNA methylation diagnostics, but over time she found herself drawn to therapeutic applications.

Zimmerman had followed antisense and RNAi since her days in graduate school, and when newly established Alnylam Pharmaceuticals began to hire researchers for its therapeutic RNAi program this past spring, she decided it was a good match. Now a scientist in the drug discovery group, Zimmerman has been working on structure-activity relationship studies of the sort that are the bread and butter of any drug discovery effort. She and her colleagues are tweaking nucleotide sequences and making chemical modifications to siRNAs in an effort to improve in vitro activity and stability, as well as other properties.

Working with the close-knit group of scientists is giving her exposure to many aspects of the research, and that validates part of her reasoning for coming to a start-up company like Alnylam. "I have several friends in the field, and my perception was that you get a better feel for the route that is taken from in vitro screening to in vivo application when part of a start-up," she says.

Many in the nascent field of RNAi are looking forward to the same journey.

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