With the use of genetically modified (GM) mice increasing in scientific research, studies on their welfare and husbandry have intensified. Sara Wells, Manager of the Medical Research Council’s international centre for mouse genetics at Harwell, talks about new evidence to show that environment plays a much bigger role than previously thought in determining the individual characteristics of groups of identical mice. With commonly held beliefs of mice breeding now being challenged, is it time to rewrite the husbandry rule books?
In the 1980s we saw the start of a revolution in genetics. No longer did scientists have to hope that, by luck, a mouse or a rat was found carrying an alteration in a gene of interest – we were now in the age of genetic engineering. Scientists had the ability to add, take away and change genes in a mammal. It became evident that mice genes were some of the easiest to change and GM mice soon became widespread in biomedical research. Mice had been bred in laboratories for many years before this, but never was the demand so high since the advent of these gene-altering technologies.
Of course, one enormous benefit of studying mice is their short generation time. Put a male and female together in a cage and as long as they are old enough, they should produce offspring in about three weeks. Breeding mice was always considered fairly straight forward, but if scientists did run into problems, there was a host of both anecdotal stories and published husbandry guides to help them. For example, if they were struggling to breed a particular type of mouse (called a ‘line’) then the advice was often to use older mothers experienced in nurturing young.
However, as the numbers of mice being used for scientific research increased, so did the issues associated with their keep. No more so than infectious diseases such as mouse hepatitis virus, which spreads easily through housed mice. These diseases, as well as making the mice sick, interfered with scientific results, confusing data and leading to inconsistencies. To overcome this, engineers designed caging systems where mice were housed in sealed plastic units, each with its own air conditioning supply. The individually ventilated cage (IVC) has now radically changed the way mice are housed. From caging where the smells and sounds of the room could be sensed by the mice, to quiet enclosures with no smells other than those produced by their cage mates.
With the escalation in numbers of different GM mouse lines and the improvements in housing, it is no wonder that the same husbandry rules, applied to breeding mice 50 years ago, don’t always ring true today. Environment and genetic background are the two major determinants of breeding ability and as progress in biomedical science has altered both, the protocols for effective breeding also need to be changed. Indeed, it is unlikely that there is a single rule book which would apply to every mouse in every unit.
“We are in the age of changing genes and changing surroundings, so we need to explore husbandry data and change our rules accordingly.”
Husbandry tales are similar to old wives tales for domestic tips – sometimes they work, sometimes they don’t. As an example, take advice over the age of mice used for mating. There are many stories that if you put mice together before puberty they ‘make friends not lovers’ and do not produce litters. However evidence from colonies in our own establishment shows that this is not true. Similarly, stories of the first litter from females always being small and often lost prove to be untrue for many of our colonies. Indeed, even the golden rule that mice from an inbred line (produced by mating siblings for repetitive generations) are all absolutely identical with identical features is beginning to be questioned.
More and more genomic and experimental data is emerging to show that the characteristics of these mice are not solely determined by genetic factors. There is evidence of both behavioural and physical differences that can be detected between inbred mice from the same parents, housed in the same cage for the same amount of time. It is truly fascinating to consider how dominance in the cage and group interaction may be responsible for such differences.
We would never encourage husbandry guides to be discounted or ignored as the welfare of the mice and the delivery of quality scientific data is always their intention. However, with such major changes to both their genetics and environment, it is not surprising that the guidelines will need to be modified. What’s more, it’s unlikely that protocols used in one facility will always be applicable in another. We are in the age of changing genes and changing surroundings so we need to explore husbandry data and change our rules accordingly.