Applying the technique
Principal investigator William Hahn, MD, PhD, (left) and graduate student Jesse Boehm are heightening knowledge about RNAi.
William Hahn, MD, PhD, a principal investigator of the RNAi Consortium created by Dana-Farber, the Broad, and other institutions to produce RNAi tools, is amazed at the early results of the search. "We've been at this only for a couple of months," he said early last summer. "Using RNAi, we're already identifying new oncogenes [cancer-causing genes] and other molecules important in cancer at a rate that we had hoped for, but didn't know if we could actually achieve," says Hahn, co-director of Dana-Farber's Center for Cancer Systems Biology.
The RNAi Consortium is creating a "library" of RNAs for silencing 15,000 mouse and 15,000 human genes. As of July, about 25,000 RNAs had been given out, mainly to researchers at Dana-Farber, Harvard, and MIT.
Hahn and members of his lab are pressing the search for genetic weak points in multiple myeloma and cancers of the prostate, breast, and other organs and tissues. Anna Schinzel, PhD, is using RNAi to screen multiple myeloma cells with the goal of identifying genes that are critical to this blood cancer. "You might find 100 genes that decrease the viability of the myeloma cells when you silence them," she says. "The hope is that drugs could be found to block the action of those genes in cancer cells, but not cause harm to normal cells."
RNAi screens become even more powerful when combined with other large-scale gene-function studies, such as "gene chip" microarray surveys that register which genes are turned off or on in cancer cells compared with normal cells.
Jesse Boehm, a graduate student in the Hahn lab, has combined information from RNAi and gene chip studies to identify a gene that appears to play a role in as many as 30 percent of breast cancers, but whose function wasn't previously implicated in cancer. "This new gene helps turn normal cells into cancerous ones, suggesting that it is an oncogene," Boehm says. "We have good reason to think that inhibiting the action of this gene is a potential therapeutic strategy." The collaboration also involved Dana-Farber's Levi Garraway, MD, PhD, and Kornelia Polyak, MD, PhD, who provided a collection of human breast tumor specimens, some of which contained the abnormal gene.
Maria Nieto, PhD, also in the Hahn lab, is hunting for genes involved in prostate cancer by looking at how androgens — male hormones — promote survival and growth of cancer cells. Current treatments for prostate cancer block or eliminate androgens in the body, which is effective early in the disease when the cancer cells need them to survive, but many tumors become independent of androgens over time, allowing them to grow and progress.
Applying RNAi to a set of 50 genes involved in androgen signaling, Nieto is "knocking down those genes in an effort to identify which ones are essential for proliferation of cells in both hormone-dependent and -independent stages of the disease," she says.
Ulrike Eggert, PhD, a chemical biologist at Dana-Farber, says the power and versatility of RNAi are "pretty amazing." She's used it in fruit flies to identify 214 genes that, when inactivated, cause cell division to stop. "Our goal was to make a list of all the genes involved in cell division — and we might find some therapeutic leads as well," since cancer cells divide when they shouldn't, she says.
- Next: The ABCs of RNAi
- Page: 1 | 2 | 3 | 4
