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RNAi Roundup: 17-Year-Old Wins $50,000 Scholarship for RNAi Cancer Experiment; MRC Offers C. Elegans RNAi Plasmid Library; Rosetta Paper Questions Gene-Specificity of siRNA

NEW YORK, May 23 - Anila Madiraju has just demonstrated that successful RNA interference experiments do not require a PhD - or even a high school diploma.


The 17 year-old Montreal student was awarded last week the Intel Foundation Young Scientist Award, which includes $50,000 and a high performance computer, for her experiment entitled "silencing cancer with RNA," the foundation announced. In addition to being one of three students to win this grand prize, announced at the Intel International Science and Engineering fair Madiraju also picked up the Seaborg SIYSS Award, which includes an all-expense paid trip to the Stockholm International Youth Science Seminar and the Nobel Prize ceremonies in December; as well as a $5,000 Intel Foundation achievement award.


The prize-winning research involves using short interfering RNA to induce selective apoptosis in cancer cells. Madiraju described in her paper, published online, how she used siRNA to silence an anti-apoptotic Bcl-2 family protein, Mcl-1L, to possibly render a pro-apoptotic protein, Mcl-1S, more effective. She also tested the effect of downregulating Mcl-1L on how susceptible cancer cells were to the chemotherapeutics paclitaxel, camptothecin, and daunorubicin. 


Madiraju used the New England Biolabs HiScribe RNAi transcription kit to make siRNAs to target the Mcl-1 gene and GFP cDNA control siRNAs. She introduced the siRNA into the cells using a lipid vector, liposomal formulation intra-lipid.


In her results, Madiraju reported that the siRNA did decrease Mcl-1L, and did induce 80 to 90 percent cell death in several lines of cancer cells, including RPMI-8226 cells, MCF7 cells, and OVCAR3 cells; and caused 50 percent cell death in the SkMel5 cells. She said it also increased the effectiveness of camptothecin and daunorubicin significantly.


Madiraju plans to go to medical school and become an oncologist. "I plan to conduct medical research so that I can contribute to the understanding of cancer and develop an effective treatment for this disease," she says on her website.


To facilitate future research on gene function, the UK Medical Research Council geneservice has now begun to offer a full library of C. elegans bacterial plasmids for RNAi.


The library, developed by Julie Ahringer and her group at the Cambridge University Wellcome Trust/Cancer Research UK Institute of Cancer and Developmental Biology, includes six sets of strains that correspond to the six chromosomes in C. elegans, the MRC said May 20. These total 17,000 different bacterial strains, corresponding to nearly every gene in C. elegans.


"Being able to inhibit gene function is critical to understanding how genes work in health and disease. Once again, the worm is leading the way," said MRC geneservice chief scientist Martin Yuille in a statement.


In the RNA interference business arena, Sirna Therapeutics' stock will not be knocked out of the Nasdaq, the Boulder, Colo., company said Thursday. The company's previous incarnation, Ribozyme Pharmaceuticals, had been notified by the Nasdaq in mid-December that it risked being delisted because it had not met the minimum requirements for trading on the Nasdaq. The company first filed for transfer of its shares to the Nasdaq SmallCap market, but then, in April, raised $48 million and renamed itself. The company's stock price has maintained a steady climb since March, from under $2 a share to the $6 range. Given the company's current cash position and market capitalization, it now meets the minimum requirements for trading on the Nasdaq.


Another growing Colorado RNAi company, Dharmacon, has continued its expansion this week, announcing the hiring of Timothy Hoogheem as executive vice president of finance and operations. Hoogheem comes to the Lafayette, Colo., company from ChannelPoint, an e-commerce insurance supplier, where he served as executive vice president of finance and chief financial officer. He has also been senior vice president of finance, chief financial officer, and treasurer of Somatogen, a biopharma company. 


Dharmacon has recently hired a slew of new executives, including Michael Deines, vice president of marketing, Rosalie Duong, executive vice president of sales, William Marshall, executive vice president of research, development, and production, and Kevin Nash, vice president and general counsel.


In the (post-high school) research arena, there continues to be a steady output of papers published on the use of RNAi to explore gene function  One paper this week, however, stands out. A group at Merck subsidiary Rosetta Inpharmatics, of Kirkland, Wash., published a paper in Nature Biotechnology online May 18, in which they report finding that RNAi silences genes other than those targeted.


The group designed 16 siRNAs to target the coding region of the IGF1R gene in HeLa cells, and 8 that targeted the MAPK14 gene. After transfecting these siRNAs into the cells, they then used microarrays to conduct gene expression analysis on these cells. They found that different siRNAs targeted to the same gene actually regulated different genes, and that the silencing of gene expression was a function of the siRNA sequence, rather than the target sequence. "Given the small degree of similarity implicated in off-target gene regulation, it may be difficult to select an siRNA sequence that will be absolutely specific for the target of interest," the researchers write. "Until siRNA design can be improved to convincingly reduce this off-target activity, incorporating multiple siRNA duplexes to silence a target gene of interest will increase the confidence with which an observed phenotype and expression pattern can be linked to target gene silencing."


These results lend weight to concerns that RNA interference results in "promiscuous genes," as one pharmaceutical researcher described it at the recent RNAi conference in Waltham, Mass. A recent paper, published by Pat Brown and colleagues in Proceedings of the National Academy of Sciences online in mid-April, used gene expression profiling to show that RNAi gene silencing was sequence-specific, but this new paper is likely to fuel added discussion on this issue.


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