Wednesday, 29 July 2015

Interview with Dr Richard Mead: Do We Still Need to Use Animals in Scientific Research?

Dr Richard Mead Kenneth Snowman and MND Association Lecturer in Translational Neuroscience

Research interests: Drug discovery in motor neurone disease (MND) from target identification, through in vitro screening to in vivo disease model testing.

Why do we still use animals in scientific research? Can we not
replicate in vivo (in whole body) work without animals?

I think the main justification for that is that we can’t replicate what happens in a whole animal in a tissue culture dish, or in a computer model. If we take, for example, the motor system, there’s a very complex interplay between, upper motor neurons and lower motor neurons and then the muscles that they connect to. There’s also astrocytes, glial cells and microglial cells which all interact within the central nervous system. People are working towards 3D co-cultures but these are composed of two or three components of something that’s way more complicated than that.

The other thing to consider, and this is true of any model of disease, is that you still have to confirm any discoveries in whatever you are modelling. So if you were modelling what happens in an animal using a tissue culture dish or a computer, you would still have to go back to the original (animal) model to confirm the findings.

Hopefully one day, we will be able to replace all animal use with other models, but we’re not quite there yet.

If a drug is found to work in an animal model of disease, why does it not always work in humans?

People tend to blame the animal model, suggesting that the model isn’t representative of the human disease and at a fundamental level this is true. We have to consider that all models have their limitations.

 A British mathematician George E. P. Box said, ‘All models are wrong, but some models are useful’, and this applies to the models used in science. So the key is to work out whether your model is useful and how. One goal of SITraN is to be experts in the models so we understand their limitations. We also develop new models that can complement the ones we already have. This allows us to look for positive results in different types of model, increasing our confidence in them.

Personally I think the bigger issue is ‘translating’ mouse results to human studies and again we try and do this in a very rigorous way in SITraN. There are many steps to progress from a positive result in a mouse study, to a positive result in a clinical trial. If a drug is found to work in a mouse, it is very hard to work out an equivalent dose in humans, this can be estimated by weight, or (more accurately) body surface area. This is based on the fact that the smaller an animal, the faster their metabolism, and therefore, the faster they get rid of a drug from their body. We can also measure the levels of the drug in our mouse models and in humans and try and match them. An even better method is to use a ‘biomarker’ (a biological indicator e.g. expression levels of a gene) to show us how much of a drug has reached the relevant tissue in the mice, then measure the same thing in patients. We are working on measures that can be used in both mouse models and in humans to measure drug effects or the disease process.

Finally, it is important to make sure clinical trials have enough participants to
detect a similar effect as was seen in the mouse model, and this isn’t always the case. So all in all, the process of translating treatments through from mouse to human is very problematic.

Can you give some examples of when animal work has helped to develop effective treatments in human disease?

Almost every disease that you can think of (which has a treatment). For example, diabetes used to be a death sentence a hundred years ago, until research in dogs identified that insulin was the influential factor, which quickly lead to treatment in humans. Both basic research (understanding how animals function), and applied research (developing drugs) are needed to make advances in the fight against diseases.

As well as this basic and applied research, any drug which has been approved for use in humans was first tested for toxicity in animals, this is a legal requirement. The testing is the result of problems identified over the years. Take thalidomide for example, this was used in humans without being tested for developmental toxicity in animals, and it turned out to cause foetal limb defects. Therefore, developmental toxicity testing in animals was introduced to check drugs had no effect on developing babies.

How is the animal work controlled and monitored to ensure it is carried safely and efficiently?

The UK has some of the tightest regulation in the world when it comes to animal testing. The UK has something called the Animal Scientific Procedures Act 1986 and also comes under new EU regulations. All work is monitored by the Home Office, every experiment is carried out under a project licence which has been reviewed by the Home Office, every individual must have a personal licence which means they’ve had accredited training, and anywhere animals are being used for scientific use must have an establishment licence. We are inspected regularly and licences can be revoked by the Home Office if necessary.

The general philosophy is that any potential benefit that each experiment could have must outweigh any potential harm to animals. The law also emphasises the rules of ‘Replacement, Reduction, Refinement’ which means we avoid using animals wherever possible, replacing them with another model, we use the least number of animals possible, reducing the number used, and we use the least distressing methods by refining the protocol. Finally the conditions in which the animals are kept and the care they receive is rigorously controlled to be of the highest standards.

Scientific animal research has been portrayed very negatively in the past, how do these portrayals differ from reality? Has the use of animals in scientific research changed a lot since?

I think the Animal Scientific Procedures Act 1986 changed things a lot, and for the better. The quality and care is what you would expect in a veterinary practice, and always has been whilst I’ve worked with animals in science. However, I think the public perception of animal use has changed. There has been a lot of negative attitudes towards scientific use of animals but that has shifted over time. Certainly, the portrayal of what happens in animal research is often not accurate at all.

One thing that’s changed over time is how open researchers are about what they do. I was always told to be careful of what I said about what I did, mainly because of the extremism which was quite prevalent then. However, society needs this research doing. We go and talk in schools and with the public, which helps to change attitudes, and we’re trying to be more open by talking about what we do.

Interview by Jodie Stephenson

Jodie is a 2nd year PhD student investigating translational biomarkers in pre-clinical models of Motor Neurone Disease. Jodie is supervised by
Dr Richard Mead and is part of the Shaw Research Group.

You can follow Jodie on Twitter @neuroruncake, LinkedIn and ResearchGate.

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