[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview again features Dr. David Baker, Professor of Neuroimmunology at Queen Mary University of London in the U.K. We spoke at the ECTRIMS conference last fall. In part one of our interview he raised the issue of why there has been very poor translation from animal models to clinical trials. Today, Dr. Baker, also known as the ”Mouse Doctor” for his work with animal models, lays out why this situation exists and what to do about it.   Interviewee – David Baker I think there’s many reasons why, and I think we all have our failings. And one can point the finger at the animal models, which a lot of the clinicians do, saying it’s the animal model’s fault, which is possible. But I think also we have to look at humans and how humans use their animal models. And then how humans translate the data from the animal models into the clinic, because I think there’s many failings along the line, and I think that’s one of the reasons for the failing between the two.   I think one of the failings is, in terms of the animal models, that when we do our animal models for these, we’re looking for mechanisms not treatments. And so about 70% of studies give drug before disease is ever induced, which never happens in a human. You know, you go after you’ve had one or two or more attacks before you’re given drugs. We also use the drugs in a way that are never used in a human, so people will do what they call a prophylactic drug where they’ll give it before the disease manifests itself. Or a therapeutic dose, which is probably when the animals are showing their symptoms. But in reality, a human would be getting steroids at that time point. They would never get a DMT. So you’re not comparing, you know, apples with apples. You’re comparing apples with pears, and I think that’s one of the problems.   And I think, you know, if you try and block an immune response from being generated, that’s quite easy compared to stopping an immune response once it’s been generated, because immunity’s about giving life-long protection against infections. And so I think it’s a different type of beast to target. So I think this is where the animal models could do it, because EAE is one of the few where you have this relapsing-remitting disease course. But it’s very, very rare that people actually start to treat in between attacks to block further relapses. I think that’s one of the problems.   The other big problem is the dose; the dose relationship between animals and humans. There’s a tendency we just keep giving more and more and more and more, and eventually the drugs will work. But you’ve got this problem that animals are very liable to be stressed, and we call it the building site effect, so construction site effect. And if you have lots of loud noises, it scares animals. They get very stressed, and your EAE just disappears. And likewise, if you just give lots and lots of drug, that probably tastes nasty. They get stressed out as well. And I think many of the so-called wonder cures – cures of the week – are because we’re just giving too much, which doesn’t have a relationship to what the human dose is going to be.   And then, likewise, I think we’ve got too much of a publication bias for the need to generate positive data. And I think what we then have to do is we have to look at the quality of the data. And I think there has been a lot of failure to replicate data. I think some of that is because some studies lack quality control, and the way I look at that – and I could be wrong; obviously it’s an opinion – but if you look at the way that EAE is scored (it’s normally a scoring system 1 to 3 or 1 to 4) and then you have your drug, which may be, you know, takes your control down f