New tools – new implications for the 3Rs

Neuropharmacologist and NC3Rs Board member, Dr Ian Ragan explains.

If something is scientifically useful but hard to do or expensive you can guarantee that a scientist will rock up and make it cheap and quick. Look at DNA sequencing which can now be done at a fraction of the cost of when the human genome was first sequenced. The second thing you can guarantee is that once we scientists have our hands on something new, just you try and take it away from us.

Recently two new things have appeared in the toolbox; the first is a new and simple method to make pluripotent stem cells from fully differentiated cells taken from newborn mice (Obakata et al., Nature 505, 641-647 (2014)); the second is a method to make targeted and precise genetic alterations in monkeys using the CRISPR/Cas 9 system that has already been used in rodents (Niu et al., Cell 156, 1-8 (2014)). These two methodologies could have huge but opposing implications for animal use which makes their near simultaneous appearance all the more interesting.

The creation of induced pluripotent stem (iPS) cells in 2006 has been eagerly seized upon as a route for creating human-cell based models of disease or tools for drug discovery and toxicology. The hope is that such models will begin to supplant animal use for the testing of drugs and chemicals. But no-one said it was easy, and the methods available to date have not made iPS cells and their differentiated progeny the routine tool of use. The extraordinary discovery that stem cells can be made from almost any cell type by simple stress treatment such as low pH may transform the field. There are some caveats however – it only works on cells from newborn mice, not adults, and its applicability to human cells is yet unknown. But these are early days, and these stress-created cells can be produced more quickly and in greater numbers than by other methods. So here is a new tool in the kit that may lead to more routine use of reprogrammed cells and hasten the development of human cell and tissue models as superior replacements for the use of animals. But, new developments can cut both ways.

The article in Cell on genetically modified (GM) monkeys has the potential to cause a significant increase in the use of non-human primates. As the authors say, “the application of monkeys in biomedical researches has been significantly hindered by the difficulties in producing animals genetically altered at the desired sites”. This is true, but ethical concerns around the use of monkeys mean that any method that makes it relatively easy to alter them genetically must be properly justified by the scientific and human health benefits arising from the research balanced against the potential harms to the animals. It is unfortunate that neither the authors nor the journal acknowledged this. The Bateson Report (2011) examined publicly-funded research in the UK using non-human primates between 1997 and 2006. It concluded that while a majority of projects could be justified on scientific grounds there was little evidence of actual medical benefit in the field of neuroscience for example, an area that accounted for nearly half of all use and was often associated with significant welfare issues. Alzheimer’s disease has benefited to only a small extent from the use of monkeys and the treatments currently under investigation in the clinic have all developed from human and GM mouse research. I doubt whether the lack of GM monkeys has limited drug development, or that many companies will be interested in using these animals. This won’t stop some researchers trying to add GM monkeys to their toolbox though on the basis that they will inevitably provide better models of human disease than GM rodents. In some instances this might be true, but the case for creating GM monkeys needs to be based on much more than a bland and sweeping generalisation. The potential relevance to human disease needs to be evaluated on a case by case basis against the known welfare costs of production and breeding, and the unknown impact of the genetic modification on the animals’ health and wellbeing. Let us hope that the arrival of this new technology does not lead to unjustifiable tinkering with the monkey genome just for the sake of novelty.