Wednesday, July 2, 2008

Biological Toolbox Expanded

It's rather shocking that news of this paper hasn't spread like wildfire already (trust Wired to be ahead of the game). However, trust even Wired to get some of the details wrong and evoke some sensationalism out of their readers by proclaiming that anyone could become immune to AIDS. Oh, and keep your eye on Sangamo Biosciences (SGMO), because this could get big.

The first thing to know about this paper is that it is, in fact, awesome. They are working on a gene called CCR5, which produces a protein normally used by immune cells in the body. The HIV virus uses this protein to infiltrate the cells and do its work. A significantly elevated portion of northern Europeans have a curious deletion in the middle of this gene called Δ32, whereas African populations do not.* The deletion results in a non-functional protein and makes the cell more difficult to hijack, but the roughly 10% of northern Europeans that have two copies of this deletion are resistant - not immune - to HIV infection.

What the researchers do is to take some well-defined bits of known proteins, and use them to design their own customized, fully pimped-out protein. For example, some proteins use bits (OK, domains) known as zinc fingers to bind very specific sequences of DNA. So this group designed some zinc fingers that would point their protein to a spot near the Δ32 deletion. Then they use another protein domain to chop both strands of the DNA where the zinc fingers bind, and then just count on the fact that DNA will repair itself imperfectly afterwards (known as nonhomologous end joining, if you're that bored). I wouldn't be telling you this if it hadn't worked, so you have guessed that their deletion confers HIV resistance to immune cells infected with it. Of course, you have to get this protein into the cells first - ironically, you deliver the gene coding it using another type of virus.

But it's all astonishingly cool, when you think about it. This brilliant little addition to the molecular biology toolbox allows the targeting of specific disruptions to literally any part of any gene. This will be used in widespread fashion by researchers looking to mutate specific parts of proteins to better understand their functions (which could potentially expand our protein-pimping garage, so to speak), and may eventually find its way where RNAi has not and find clinical applications not just in AIDS, but in a wide variety of diseases and potentially even in stroke.

* As an aside, some might wonder if the European/African Δ32 divergence was caused by natural selection by other diseases, specifically the Black Plague, but the frequency of the deletion was similar in DNA from Bronze Age samples. So, no.

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