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[Update below]

Nature has a short item on the Pfizer (NYSE:PFE) paper that questions the reproducibility of some key sirtuin work (covered here and here). There are some good points to temper the pessimism. Leonard Guarente of MIT, a key pioneer in the field, says:

". . . that the latest findings are neither surprising nor worrisome. The compounds may work only with fluorophore-conjugated peptides in vitro, says Guarente, but the situation is different in cells and in animals. The Nature paper, among others, went beyond the test tube and indicated that SIRT1 was more active in cells and in animals after application of the Sirtris (SIRT) compounds. Furthermore, resveratrol administration made no difference to the lifespan of yeast that did not have Sir23, indicating that the compound's action depends on this gene.

According to a statement from GlaxoSmithKline (NYSE:GSK), Ahn's conclusion "ignores any possibility of direct activation of SIRT1 that may occur in a cellular environment that is not reproduced in vitro".

True, but there's still that problem of the Pfizer group not being able to reproduce the in vivo effects, which to me was perhaps the most worrisome part of the paper. Now, it's worth remembering that animal studies are not the easiest things in the world to do right, since there are so many variables. Small differences in animal strains and the like can sometimes throw things off severely. Even the Pfizer group admits this readily, with Kay Ahn telling Nature that "every in vivo experiment is a little bit different" and that "Under our conditions we didn't see beneficial effects, but we don't want to make a big conclusion out of those results."

That's an honorable way to put things, I have to say. Rather less honorable, though, at least to me, is David Sinclair's response from the Sirtris team. See what you think:

A possible explanation for the discrepancy, says Sinclair, is that Ahn and her colleagues did not provide information on the characterization of the compounds, which they synthesized themselves. So there is no way of knowing how pure they were or whether they're the same as those made by Sirtris. "The fact that mice died indicates that there may be an issue with purity."

That's. . .not so good. In fact, it comes close to being insulting. Although I say a lot of uncomplimentary things about Pfizer's management, the fact remains that they have a lot of very good scientists there. And I assume that they can reproduce Sirtris's published procedures to make the sirtuin ligands. If they can't, frankly, that's Sirtris's fault. Everyone (well, everyone competent) checks out compounds thoroughly before putting them into an animal study. Asking "Are you sure you made the right stuff?" at this point is really a bit much, and doesn't do anything to improve my opinion of Sirtris. (Which opinion actually was pretty good - until recently).

Update: "A Storm in a Teacup" - So says GlaxoSmithKline CEO Andrew Witty about the Sirtris controversy - see this Forbes story for more. I hope he's right. I actually would like to see good things come out of sirtuin research - the biology's clearly interesting enough. And I would like to think that GSK didn't blow $720 million, because we could all use that sort of money these days. This story will only be settled for sure in the clinic, with the agents the GSK is developing. Good luck to them. I fear that they might need it, but I hope that they don't.