'Of Mice and Men and Medicine', by Rhianna Boyle

Photograph by Mycroyance. Reproduced under the Creative Commons Attribution 2.0 Licence.

Many of us are genetically predisposed to at least one health problem, but you can rest assured that at least you are not alone in your suffering. Whatever your Achilles heel, it’s likely that in a medical laboratory somewhere, there is a group of mice or rats with the same symptoms. For example, the Jackson Laboratory – a worldwide supplier of lab mice - offers a cornucopia of human disease models, replicated in rodent miniature in their trademarked JAX® Mice. Their website lists available strains, together with information on whether they are currently ‘live’ or ‘cryopreserved and ready for recovery’.

The degree of similarity between mammalian genomes is high enough that the genetics of many human diseases can be easily replicated in rodents. There are JAX® Mice with the most common human diseases, including cancer, Alzheimers, cardiovascular disease, and diabetes. You can also purchase mice with Down syndrome, fragile-X syndrome, dwarfism, colour-blindness, endometriosis, migraines, and epilepsy, to name just a few. Some strains are developed to replicate rare or ‘orphan’ diseases, for example maple syrup urine disease, a metabolic condition which makes sufferers’ urine smell like maple syrup; or fatal familial insomnia, a hereditary condition in which successive generations of affected families — both human and rodent — die in middle-age from a complete inability to sleep.

Some scientifically afflicted rodents have conditions that mimic what seem to be specifically human problems. Although it sounds like an anthropomorphic joke, there are mice with carpal tunnel syndrome, mice with acne, and mice predisposed to alcohol dependence or tobacco addiction. Other mice replicate the genetics of eating disorders, schizophrenia, depression, ADHD or susceptibility to autistic spectrum disorders, although naturally the cultural aspects of these conditions can’t be reproduced.

It is unlikely that they are preoccupied with feelings of worthlessness or existential angst.

For example, ‘anorexic’ mice will starve themselves by exercising at the expense of eating, but they are not preoccupied with body image or influenced by popular culture. Mice carrying genes associated with depression can show symptoms such as reduced cognitive abilities, high fear and anxiety, and a reduced preference for sugary drinks; the latter mimics the inability of depressed patients to find pleasure in normally rewarding activities. When ‘depressed’ mice are subjected to a swim test, that is, forced to swim to survive, they have a tendency to give up earlier than other mice, but will swim for longer when put on antidepressants. However, it is unlikely that they are preoccupied with feelings of worthlessness or existential angst. Mice with genes associated with schizophrenia will show the neurobiological markers of the illness, as well as symptoms like poor memory, aggression, and hypersensitivity to their environment. It doesn’t appear that they experience hallucinations or delusions, although in their case, believing they are part of a sinister mind control experiment conducted by scientists wouldn’t be at all delusional.

However, these standard commercially available lines might not suit the needs of all researchers. For this reason, many commercial lab animal suppliers offer individualised services to produce bespoke rodent lines. The company SAGElabs, for example, retails what it describes as ‘off-the-shelf’ and ‘custom bred’ rats. Until recently, genetic engineering techniques have been more easily applied to mice than rats, so mouse models go even further. As with some standard lines, these customized models are created using genetic engineering techniques to produce what are known as knock-in\knock-out, or transgenic mice.

Basically, these techniques involve isolating the desired gene and injecting it into an embryonic stem cell, then raising the cell in a mouse. In some of these mice, the engineered stem cell will end up as testes and therefore sperm cells, which means that the mice will pass the gene on to their offspring. The inGenious Targeting Laboratory spruiks such services with the slogan ‘You Think It Up, We Knock It Out’, while the website for the company Cyogen currently offers a promotion on ‘inducible knock-out, knock-in and humanised models – 20% off!’.

A humanised model is one in which the mouse or rat carries functional human genes, cells, organs or tissues. For example, mice with a mutation that wipes out their own immune system can be injected with human immune cells to produce a working replica of the human immune system. Such immunodeficient mice can also be used to grow, for example, grafts of human foetal liver, or they can have human tumours inserted without their immune system rejecting the tissue. There are rats that carry a human gene associated with Parkinson’s disease. Humans and rodents have been uncomfortably close for millennia, but recent medical advances have brought us together in a more intimate way.

An immunodeficient mouse features in the notorious photograph of the mouse with a human ear shape grafted on its back, taken in 1997. The photograph has become a defining image of the last century. Although no human tissue was involved (the experiment used cow cells on an ear-shaped mesh, and the tissue was never transplanted), the image has come to symbolize both the cruelty we are prepared to inflict on rodents, and our disgust when the boundaries between our two species are transgressed. Apparently for both of these reasons, it was used in an ad campaign against genetic engineering, despite the fact that the mouse was used was a naturally occurring mutant strain, and no genetic engineering was used.

The ancestors of modern lab mice were first domesticated as pets in Asia during the 17th and 18th centuries. These animals were bred largely for their unusual coat colours, including albinism, and for other rare traits. For example, Japanese ‘waltzing mice’ walked with a circular motion that resembled dancing—the result of an inherited neurological defect. Fancy mice breeding became popular in England and the United States during the Victorian era. The name ‘fancy’ didn’t refer to the fact that the rodents were bred for their decorative qualities — in this case, the word meant hobby. A recent genetic analysis of modern lab mice shows that they are a hybrid of four wild strains from across Europe and Asia, probably due to deliberate and/or accidental cross-breeding by fancy mouse breeders. Lab rats are also thought to descend from Asian ancestors that were bred as pets, although rats were also caught and sold in Europe for the sport of rat-baiting, which involved watching a terrier kill an arena full of rats, so domesticated rats may also have European origins.

Fancy mouse and rat breeding survive as hobbies today, and some enthusiasts even sew and sell tiny, seasonally themed dress-up clothes for rats. Although a degree of anthropomorphism has permeated the pastime, for the most part, the domestication of rodents has not given them the privileged cultural status afforded to other domestic pets. Breeding for physical traits exploits rodents’ large reproductive output and short life cycles – the more young that are produced, the greater the chance of producing rare coat colours – but also requires culling many animals who aren’t of genetic value.

Victorian-era fancy rodent breeding was an unscientific enterprise, in which half the fun was probably the element of surprise. But around the turn of the century, the rediscovery of a long-neglected paper written by monk named Gregor Mendel changed everything. Mendel’s famous work, on the inherited characteristics of peas, predicted the existence of genes, and it was found that similar experimentation could be done with mouse coat colours.

In the United States, much of the early scientific breeding of lab mice was done by Clarence Cook Little, founder of the Jackson Laboratory, and Miss Abbie Lapthrop, a retired schoolteacher and fancy mouse enthusiast. Some of the inbred mouse lines they produced were notably cancer-prone, and these became the first strains used in the lab as human disease models. Albino strains began to be bred for science in the 1920s. It’s unclear exactly why albinos were favoured – presumably it wasn’t just because they matched scientists’ lab coats – although some have suggested it was because albinos tended to have docile temperaments.

Lab rodents are now well and truly a commercial product, and as with many other products, there are accessories to match. Researchers can purchase the Rotamex-5, which “measures coordination in up to four rats or mice by recording the latency to fall from a spinning rod”. Then there’s the PACS-30 Avoidance Monitor, which produces an electric shock to see whether rodents can be trained to either avoid or put up with pain. The Vogel Test Anxiometer-102 is “designed to induce anxiety within the subject” by shocking rodents after they take a certain number of sips from their water dispenser. The Anxiometer (note the name) allows researchers to rate the performance of anti-anxiety drugs by comparing the drinking behaviour of “punished drugged rats” to that of “punished non-drugged rats”.

It seems there is a lot going on in the minds of rodents that remain mysterious to us.

Even the accessory that is meant to provide rodents with fun and fitness – the exercise wheel – only allows for repetitive, pointless activity. At least, this was the popular wisdom until earlier this year, when Dutch researchers published a three-year study in which wild mice were given the opportunity to run in these wheels. Film footage of the wheels, which were placed in parkland and sand dunes, showed wild mice voluntarily entering and running in them on hundreds of occasions. Also filmed entering the wheels were several shrews, rats, snails, slugs and frogs. The clincher for the study was that, with the exception of the slugs and snails, individuals of each kind of animal were filmed leaving a wheel, then re-entering it shortly afterwards and continuing to run. This suggests that the activity is intentional, perhaps even enjoyable, although the researchers are at a loss to explain why. It seems there is a lot going on in the minds of rodents – as well as frogs and shrews – that remains mysterious to us.

Another recent study shows how little we understand about life as a lab mouse. Thus study shows that mice react differently to male and female lab technicians, in ways that cast doubt on a vast body of medical research. Mice that were subjected to pain in the presence of male researchers exhibited a lower level of pain – as measured by the mouse facial grimace scale – than mice subjected to the same procedure in the presence of female researchers. The mice showed the same response when the pain was inflicted in the presence of teeshirts worn by either males or females, which suggests they were responding to odour cues.

These results are probably not due to a rodent preference for human men. Rather, a reduced pain response can result from increased stress. The odours produced by human men are very similar to those produced by other male mammals, including mice. It seems that this ‘male smell’ puts both male and female mice on edge, perhaps because they associate it with competitive violence or sexual aggression. The worrying thing is that in the numerous studies that measure pain in rodents, controlling for, or even recording, the gender of the lab technicians has not been a consideration.

As well as potentially undermining a large chunk of western medical science, this study shows the persistence of wild instincts despite more than 300 years of captive breeding. Laboratory mice don’t have to fight for mates or food, but it’s nice to know that should the end of modern civilisation require them to fend for themselves, they still have an instinct for self-defence.

In an unconventional experiment, zoologist Manuel Berdoy released lab rats onto a fenced, abandoned farm and made a film about the results (The Laboratory Rat: A natural history, 2004). Hefound that the rats quickly adapted to the ‘wild’ environment, digging tunnels for protection, avoiding cats, and establishing a stable social hierarchy. Two strains of lab rat were introduced into the new environment, but when the next generation was born, it became apparent that some rats of the albino Wistar strain had mated with their Lister hooded counterparts, reuniting inbred genes that had been segregated for hundreds of generations. The resulting offspring could be described as mongrels, but on the other hand, they could be seen as a step towards inbred rats reclaiming their former, genetically diverse, glory.

This column originally appeared in The Lifted Brow #24: The Medicine Issue.

Rhianna Boyle is a zoologist and writer. A previous column for The Lifted Brow appears in the Best Australian Science Writing 2013.