You may well remember Amgen’s statement in 2012 about how many academic papers they were having trouble reproducing. Not everyone has taken it seriously, since they didn’t provide specific details, just an overall count. (On the other hand, a lot of people inside the drug industry just nodded their heads, having had similar – and similarly nonpublishable – experiences themselves).
Now the company is back with some chapter and verse, although I wish they had even more. This newly launched site at Faculty of 1000 is going to be dedicated to this sort of thing, and it will be very interesting to see how it fares. The first entry is on GPR21 knockout mice. These were reported in 2011 and 2012 to show increased insulin sensitivity and glucose tolerance – and that first reference, by the way, is from a team at Amgen itself (the second is from UCSD and Scripps). It turns out that the earlier knockout animals also had another gene disabled (Rabgap1), and generating the knockout through another technique (TALEN) gave a cleaner animal model that unfortunately shows no such effects on glucose and insulin.
The second entry refers to the ubiquitin-specific protease USP14, which was reported in 2010 as a possible target in neurodegenerative disease. Inhibiting the protease with a small molecule, it was believed, would speed up the degradation of harmful proteins like tau (which otherwise would be de-ubiquitinated and saved from destruction). The Amgen group, though, could not confirm any role for USP14 in degradation of such proteins, despite several attempts. This adds to a 2012 report that USP14-deficient mice didn’t seem to show any effects on tau levels, either.
And finally, there’s a follow-up on the effects of an LXR/RXR agonist on the levels of beta-amyloid in the brain and CSF. (My own opinion: that’s just what you need to increase the success rate of an Alzheimer’s program – go after a centrally acting nuclear receptor target. Not only are you stumbling around in a blacked-out basement, you’ve tied your feet together as well). This was the 2012 bexarotene paper, which I blogged about here. That one picked up criticism from several other labs who could not reproduce its findings, so this Amgen report (they couldn’t, either) doesn’t add much to the story, from what I can see.
So while I’m glad to see these, and also very glad to see the F1000 site that gives these a home, these don’t seem to have as big an impact as one could have expected. Both the bexarotene work and the USP14 results had been dented pretty badly already, and those reports didn’t need this platform to appear in, either. What I’d like to hear about – and I’ll bet I’m not alone – are some of the things that we didn’t know were problematic. Will those start to appear?