Q&A: Vicky Robinson – answering a difficult question with the 3Rs

A researcher handling a mouse. 

The use of animals in research is one of the most difficult and emotive ethical dilemmas confronting the life sciences. Few of us are comfortable with the thought, but, on the other hand, we want new treatments and cures for disease and injury, which can, –of course, benefit animals as well as humans.  The uneasy crux of the matter is whether the health benefits of research – which are often hard to quantify – justify the means.

Many governments, research funders and scientists across the globe believe that ultimately, they do – provided animal suffering is minimised and there is no viable alternative method of answering the experimental question.

To ensure adherence to those two provisos a number of countries have adopted the 3Rs – Replacement, Reduction and Refinement – as guiding principles, enforced by law, for using animals humanely in research. The 3Rs require researchers to replace animals with alternative methods wherever possible, to refine their procedures to minimise harm to the animals, and to find ways of reducing the numbers used.

In the UK, the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) – established in 2004 with funding from the government, industry and charity sectors (including the Wellcome Trust) ­– funds research in the 3Rs and works to advance them in science practice. I met the Centre’s chief executive, Dr Vicky Robinson.

The difficult question first: will we ever be able to replace animals entirely?

I suspect not in this generation, but in the future I think there’ll be a real revolution and people won’t need to use animals as much, if at all.

What alternatives are there currently?

There are lots of alternatives available, many being developed through the work of the NC3Rs.  The computing power we’ve got today means researchers can use sophisticated computer and mathematical models of body systems. They can use tissue engineering to grow organs and tissues from stem cells in the lab, or in-vitro techniques to test the effect of drugs or chemicals on human cells in test tubes. In some circumstances scientists can use human volunteers instead of animals.

Would the science be as good using those methods?

The science could well be better. There are important physiological differences between animals and humans – they don’t get the same diseases, or the diseases don’t behave in the same way. Mice don’t get asthma, so the rodent model of asthma doesn’t mimic what happens in people very exactly.

Last year we funded some researchers to create tissue-engineered models of the human asthmatic airway to use instead, and we’re hoping they’ll yield more relevant information. That’s attracting a lot of interest from academics and from industry. Beyond improving animal welfare, the 3Rs are a legitimate scientific goal in their own right with definite scientific and business benefits.

Shouldn’t drugs be tested on a whole animal, rather than in a test tube, in case there are unexpected systemic effects ?

Not all adverse or unexpected effects will be picked up by animal tests, although many will. And many pharmaceutical drugs that seem safe and effective in animal studies fail in the clinic, so there is a real drive to find better, more predictive models. Many people will recall the 2006 TeGenero clinical trial of a monoclonal antibody drug. It had seemed safe in animal studies, but the human volunteers experienced serious side effects from a ‘cytokine storm’. We’ve just made an award through our new open innovation initiative, CRACK IT, to a group of scientists to improve our ability to predict cytokine release in response to an antibody. The aim is to find better ways of testing the human immune response in a test tube – before the antibody is put into actual people – using immune cells from human volunteers. They stimulate the cells with an antibody measure the cytokine release.

Even where the use of animals is unavoidable a lot can be done to reduce the numbers used. The NC3Rs has been working with around 20 companies developing monoclonal antibodies, and just by encouraging them to share data we’ve been able to identify opportunities to reduce the number of monkeys used by 64 per cent.

That was one of the Crack It Challenge competition winners, I believe. Can you tell us a bit more about the competition?

CRACK IT is a new initiative which focuses on connecting scientists from different sectors and disciplines. It includes a new competition CRACK IT Challenges which is designed to solve business challenges with a 3Rs theme. We worked with companies from the pharmaceutical, agro-chemical and consumer product sectors – companies like Astra-Zeneca and Unilever – and came up with six big research questions in the 3Rs. Then we challenged researchers from the bioscience, engineering and mathematics communities to address them.

We gave five winners £0.5m to £1m each in February for research in areas such as developing new tools to study bipolar disorder without using animals. And because they’re sponsored by industry, academics will be able to use data, compounds, chemicals and equipment they would normally find it hard to access. This will help them test their models and think about commercialisation.

Let’s talk about ‘refinements’ now. What kind of ‘refinements’ can minimize animal suffering?

Researchers often will pick mice up by the tail so that they can’t bite. The NC3Rs is funding a top animal-welfare scientist in Liverpool, to look at indicators of stress in mice picked up by their tails including their behaviour and hormone levels. This research has already shown that those mice are anxious and timid. By contrast mice who were caught by being gently cupped in the hands or a plastic tube were calm and unafraid – they actually come up to the researcher’s hand.

That was published in Nature Methods and won our 2010 3Rs Prize. Again as well as improving the animals’ well-being there’s a scientific impact. Lots of experimental parameters can be affected by anxiety. The science will be more useful if you use a calm, happy mouse.

Can you tell when a mouse is happier?

There’s been a complete transformation in our understanding of animal pain over the past five years. Not that long ago, people believed rodents don’t feel pain because they don’t show obvious signs of it. But rodents are prey animals, so they’ve evolved to conceal signs of pain that would make them vulnerable to predators.

We funded some research into this area. A group in Newcastle have looked at hours and hours of video footage of rats after surgery, with and without pain relief. This showed that distinct behaviours like back arching and abdominal twitches could be identified that were associated with rats experiencing pain. That’s given us evidence that rats do feel pain – and a measure for quantifying it. We’re now funding further work looking at the best kind of pain relief to give to rodents involved in specific types of research? What dose? And how long for?

Some other research showed that mice pull a particular face after surgery – a ‘pain face’, suggesting that, just like people, they have an emotional perception of their pain, as well as a physical one. And we’re now funding work to look at whether that’s also true in rabbits, other rodents and monkeys.

Does a happier animal really make for better science?

Yes, there is a general view that this is the case and more and more evidence to support this.  For example, we have been working with a major pharmaceutical company to come up with a way of allowing them to monitor the behaviour of mice and record from their brains in studies of diseases such as Alzheimer’s. At the moment to do this the mice have to be housed on their own and for social animals such as mice this can be quite stressful. In addition the tests are done during the day but mice are nocturnal so again this can be quite stressful because it may mean their sleep is disrupted. Plus, the mice have to be handled a lot which they don’t like very much. So we are funding some work to design a way of doing these studies at night when the mice are normally active and in a way that allows them to remain with their cage mates and not have to be handled as much. We believe that the mice will be happier and as a result the data obtained will be better and not compounded by the effects of stress.

Is it better to use a rat than a monkey?

I think in some cases it is on balance. We’ve been involved in some research to look whether rats can be used instead of non-human primates to test whether a new drug that acts on the central nervous system might be abused by patients. We have shown that rats give you information that is as predictive for humans as monkeys.

From a welfare perspective it’s probably better to use a rat than a monkey. I think you have to be slightly pragmatic. You have to look at the whole life experience of that animal – its cumulative suffering – not just at the time it is being used in the experiment. A lot of monkeys are bred overseas, often in facilities that wouldn’t meet UK standards. They’re are then transported long distances to labs around the world and this can be stressful. It’s also difficult to keep a monkey happy in a lab environment, in terms of giving it enough space. A rat, on the other hand, you can breed in-house or locally avoiding long distant transport, and they’re much easier to accommodate  in a lab environment than a non-human primate. So it’s a more humane choice but it is important to look at things on a case by case basis.

Finally, what’s the biggest change you’ve seen in research practice with regards to animal use?

For me the most important change in the last five years is the fact that the 3Rs are now a legitimate scientific goal. We’ve got big-name scientists involved in our agenda, which has helped give it a credibility that it hasn’t had in the past.

Scientists today are also much more willing to critique the models they use, proactively think about alternatives, and see that they have a role in developing the alternatives. It’s really important to maintain that momentum.

The NC3Rs is part-funded by the Wellcome Trust. Find out more about the Centre on their website. 

Image credit: Wellcome Library, London