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LC: My Principal Investigator at the Fred Hutchinson Cancer Research Institute works on translation in cancer. And when I told him I was going to interview Joan Steitz, he told me to ask whether you think RNA will be druggable in cancer.
JS: I mean you would want it to be specific for the cancer cells. That’s the difficult part… When you say “Is RNA druggable?” I do have an opinion on that, and it comes actually from a meeting with the board of an NIH consortium grant that has people from various parts of the country who are studying various aspects of RNA biology. I heard a talk by someone at Duke who is an NMR structural biologist where he took a region from the HIV genome called the TAR which makes messages, and he had put that together with a number of different drugs. What was impressive about his finding was that every single drug that bound to this small hairpin loop element in the HIV genome gave a different structure to the RNA based on how the drug made its molecular contacts.
So RNA is not like a protein where you’re looking for a drug that’s going to go in and sit in a particular spot that’s a well defined spot–RNA molecules are very plastic, and so every one of these structures were different. And if you think about what that means in terms of the druggability, I think it could be sort of skittish.
In terms of RNA and blocking the access of things to RNA or DNA molecules, that’s a whole other question and I’m very excited by the whole antisense field and what people have been able to do and maybe things can be blocked with morphed oligonucleotides that prevent ribosomes from scanning through to the start site on various genes that are important for cancer. There are a lot of people doing a lot of creative things and that’s great.
LC: I think Professor Anna Pyle had us read a paper on a low-ph targeting transmembrane portion with an antisense.
JS: Oh that’s Don Engelmen’s discovery to get things across membranes very specifically into cancer cells because they tend to be more acidic than other cells, so that’s very cool.
LS: More broadly, what sort of things do you still wonder about RNA? What are your big unanswered questions or areas?
JS: Yeah okay, the sort of questions I think about now have to do with this exploding universe of noncoding RNAs and what they’re all doing. Is it really that they are doing something or is it the process of their synthesis and then their degradation that’s important? And actually one thing that Radhakrishnan pointed out in response to a question yesterday was that Sydney Brenner, another great person who recently died, spent a lot of time after the discovery of introns and the huge size of introns making the point that the pufferfish has a genome that’s only about one fifth the size of the most closely related fishes. It has small introns and much less intergenic space, and yet the pufferfish looks and acts and can do what those other fishes do. So is it really all just junk? Even if it’s junk, how does the lifecycle of the cell cope with all this junk? And the more junk you have, the more likely you are to make mistakes in initiating transcription and make RNA molecules that really don’t do much. But we’re learning more and more about what they do, so you’ll be learning that in class soon hopefully.