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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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November 17, 2004

RNAi: The Awkward Age

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Posted by Derek

A notable feature of 21st century molecular biology (so far!) is the emphasis on RNA. I've written before about RNA interference, a hugely popular (and hugely researched) way to silence the expression of proteins in living cells. Wide swaths of academia and industry are now devoted to figuring out all the details of these pathways, key parts of which are built into the cellular machinery. They turn out to regulate gene expression in ways that weren't even thought of before the late 1990s, and I've said for several years now that this field is the most obvious handful of tickets to Stockholm that I've ever seen. (Naturally, there are some worries that the whole field has perhaps been a bit over-promoted. . .)

Shutting off the production of targeted proteins is a wonderful thing, both from the basic research viewpoint and the clinical one. The more control you can have over the process, the better, and RNAi has been extremely promising. But as we're learning more about the system, complications are creeping in. Don't they always. . .

It turns out that the small interfering RNAs that are used, and are supposed to be the most efficacious and the most specific, aren't always what they seem. A disturbing recent study used one targeting luciferase, a firefly protein with no close relatives in the human genome. But applying it to the human-derived HeLa cell line showed effects on over 1800 genes - some of which only showed up at high concentrations, true, but none of these would have shown up at all in the ideal world we might have been living in for a while. There have also been experiments with RNAs that have deliberately made with slight mismatches for their intended target, and some of them work rather too well.

Finally, as I mentioned about a year ago, there are reports that these small RNAs can set off an interferon response, suggesting that the technique can cause cells to respond as if they're under infectious attack. As you'd imagine, this can also complicate the interpretation of an experiment, especially if you're already targeting something that might interact with any of these pathways (and plenty of things do.)

None of these yellow flags are particularly large, but there are several of them now and probably more waiting to be noticed. (A good brief roundup of the situation can be found in the November issue of Trends in Genetics, for those with access.) Perhaps as we learn more we'll find ways to obviate these problems. If there's one thing for sure, it's that we haven't figured out all the tricks that RNA is capable of. But the companies that are racing to get RNAi therapies into the clinic are watching all this a bit nervously, hoping that they're not going to be those fools that you always hear about rushing in.

Comments (3) + TrackBacks (0) | Category: Biological News


1. Chris on November 19, 2004 11:46 AM writes...

What then, is your opinion of the article in the current issue of Nature "Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs", in which Alnylam used siRNA modified with a cholesterol moeity to achieve uptake into cells? The target was apolipoprotein B, allowing them to lower cholesterol in mice.

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2. Derek Lowe on November 19, 2004 12:58 PM writes...

Thanks for pointing that one out to me; I'll try to do a separate post on this next week.

That group reported some of the properties of these things earlier this year in a paper in Bioorganic/Med Chem Letters. It's certainly the best in vivo siRNA data I've seen, not that there's a huge amount in the open literature yet. But it would be interesting to see what happens in, say, a four-week toxicity test, wouldn't it? No doubt Alnylam is trying to find that out as we speak. . .

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3. caltechgirl on November 23, 2004 8:52 PM writes...

Well, honestly, Derek, I'm not too worked up about it. The last "big thing" was gene chip studies, but as more and more of them have gotten funding and the results come out, it's more and more clear that the results are somewhat arbitrary, at least in the studies I'm most familiar with, mostly those relating to Schizophrenia. There was a great review of this in Nature Neuroscience this summer, but I don't have the cite at hand. I think that as we learn more about siRNA technology, we'll also learn its limitations.

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