This piece in STAT is well worth a read. The author, Adam Rosenberg of Rodin Therapeutics, is ready to ditch rodent-centric models for human CNS disease, and I can see where he’s coming from. I’ve often said that when I think back on my Alzheimer’s and schizophrenia drug discovery days (back when I was first starting out), and I remember all those compounds I made whose crucial assays were things like whether a mouse ran into the dark half of a cage or not, it makes me want to bang my head on something. The Alzheimer’s work, for example, was literally that: mice in general have an instinct to run into a dark area when they get illuminated. But if you electrify the floor of the dark area so that it tingles their feet, they can learn not to do that. Young mice, though, forget that a lot more easily than adult mice, so our assay for our Alzheimer’s candidates (which were selective muscarnic antagonists) was to give them to young mice to see if they could remember better not to run across the metal strips when the light came on in their cage.
Now, you tell me what relevance that has to Grandma forgetting where the house key is. These were not transgenic mice; they were not suffering from anything remotely like Alzheimer’s. All we knew was that for some reason young mice had less robust memory formation, and that the human disease we were targeting most definitely had effects on memory, so, well. . .Even at the time, I had my doubts, of course, but (1) I was just starting out in the business and wasn’t in any position to tell anyone how to do things any better, and (2) I had no ideas about how to do things better, anyway. I’m not sure if I still do, other than to stop pretending that some of these mouse assays are real just in order to reassure ourselves. And that’s where Rosenberg is as well, it looks like:
To begin, it helps to have this discussion frankly — and to have it with investors, board members, and executive teams. We must all be hesitant to overweight behavioral phenotypes when making key decisions in late-preclinical neuroscience drug discovery. . .
We’ll never know how many compounds were moved into the clinic based on questionable behavioral data. We’ll also never know how many otherwise promising compounds were shelved for failure to show “efficacy” in improving cognition in a flawed mouse model.
He’s suggesting that looks at neuronal circuitry and function (while still quite black-boxy) are still better than trying to infer efficacy from behavioral models, which are a whole level (or two or three) removed. Basically, he’s calling for people to get real and admit that we don’t understand these things very well, but that one thing that we probably do understand is that mouse behavior doesn’t really translate well to human behavior. The sorts of assays that Rosenberg is proposing are a bit fuzzy and hard to interpret, but what do you think we have now? They at least would seem to have a somewhat better chance of translating to something real.
That would be quite a step for a lot of people in the field, though. I don’t know of too many who would stand up and defend the rodent passive avoidance response assay or the Morris swim maze or what have you as great front ends for Alzheimer’s research, but at the same time, they would be rather nervous about abandoning them completely. But by now, I think this stuff really does probably do more harm than good: as Rosenberg says, these models reassure us when we have no real basis to be reassured. In the worst cases, we’re spending time, effort, money, and mice in order to fool ourselves.
This is not a blast against all mouse models or animal testing in general. There are many areas where rodent models are really useful – in fact, crucial – and others where they have their false-positive problems but are still good gatekeeper assays. But human CNS work dealing with higher brain functions (memory, cognition, and behavior) is just not one of those areas. A crap assay is *not* better than no assay at all.