The Hole Story:
The Mouse Model of Cancer ctd.
Jimmy the Elephant Mouse
Most of Greenoak's experiment's are carried out on mice. He finds the animals to be extraordinary in many respects. A few years ago he noted in the colony of inbred hairless mice, a hairy mouse one that had reverted back to being hairy as the species had been before the mice mutated to being hairless many generations before. This mouse grew to be very big and very fat and he called him Jimmy, Jimmy The Elephant Mouse. Because it is very important to try and understand the influence that hair follicles have on susceptibility to skin cancer, Greenoak bred other hairy mice from Jimmy. Then he began an experiment which involved shaving these hairy mice and irradiating them with UV light and comparing them with the hairless mice. He did this with albino hairy mice (mice without any colouring) and with black hairy mice. To his surprise none of the hairy shaved mice got any tumours whatever, whereas the hairless mutant mice, as usual, got 100% incidence of tumours.
This was a rather startling result which he found very difficult to interpret so he went over to the genetics section of the Department of Animal Science where he was advised that the hairy mouse probably had what is called a transposable genetic element. What apparently was involved was that an insert of genetic information into the genetic makeup of the mouse, which had produced the strain of hairless mice, and this had spontaneously jumped out and resulted in a hairy mouse again (a 'revertant' hairy mouse).
The following year he went to America and discussed this with a number of people and on his return to Australia was contacted by a group in Boston that had been looking at the hairless mutation for years. They were almost certain that this mutation was originally caused by the insertion of a retrovirus into the genes. The Boston team were able to show that the hairless mutation was indeed caused by a retroviral insertion, a mouse leukemia virus.
Somewhere in its evolution this virus had gone to live in the DNA, in chromosome 14, says Greenoak. It seems not to be contagious. We don't really have any idea where it comes from but it is only the second time that it has ever been shown that what was originally considered to be a spontaneous mutation was actually caused by a virus. This has implications for our notions of evolutionary processes. So we were all very excited about this.
This has initiated a full scale collaboration with the people in Boston and also with the National Institute of Medical Research in London. This collaboration is addressing the cause of the mutation which is indicated by a little bit of the virus left in the genetic structure. This bit of virus is being used as a marker for using genetic engineering techniques to find out what the gene which causes hairlessness is programmed to do. It is hoped this might turn out to be something which accounts for the difference in susceptibility to skin cancer between the hairy shaved mice and the hairless ones.
There is a possibility that the reason the revertant hairy mouse is not susceptible to skin cancer is purely physical. That is, at the microscopic level there may be something about the development of hair follicles in a normal mouse, and with the degeneration of hair follicles in the mutated mouse, that may lead to a susceptibility. Recent research on cells of hair follicle units and the epidermis (a part of the skin) suggest that it is possible that these cells are involved in, or strongly influence, the susceptibility of these mice, and perhaps other animals, to skin cancer.
In the hairless mice the hair goes through a cycle of growth and degeneration and there is a point in this cycle when the hair follicle as a whole is extremely distended (stretched out). At this point it is important for the further growth of the hair that the hair follicle doesn't break. What happens in the mutated mouse is that it does break and so the hair doesn't grow any more. The gene that has been mutated by the virus may cause this break by a deficiency in the production of a particular protein or tissue and this is a line of investigation that Greenoak is pursuing.
The puzzle is pretty straight forward once you have got some way of accessing the genetic material, he says. When you know a bit of the code you can make probes to get in there and work out the genetic sequences around that point. Then you can translate those sequences into their protein part and find exactly what they are producing. The trick is to find the right spot to start with and that is what the virus enables us to do. If the problem turns out to be with a deficiency in the production of a substance, for instance, then it might be possible to produce it artificially using genetic engineering techniques.
Skin cancer is not only a problem for humans but also a significant problem in the animal populations of Australia. Cattle, sheep and goats all suffer from it and if there is a gene that is producing something protective in one species of animal it is possible further down the track to actually genetically engineer animals by inserting the protective gene from hairy mice into these susceptible farm animals to give them the same protection. Greenoak thinks it would be unlikely that such a treatment by genetic engineering would be given to humans. However, if mice skin works the same way as human skin then the substance that the protective gene manufactures could be made artificially and perhaps used therapeutically.
UV radiation has a significant economic effect on farm animals in Australia by causing skin cancer. There is a particular problem with sheep after their tails have been docked. The vulva is then exposed to sunlight and they get skin cancers. Hereford cattle also get skin cancers and eye cancers. Animals with pale non-pigmented skin tend to be effected. Tumours sometimes appear on the udders of cows and goats because they cannot protect their udders when they lie down. In goats there is also a melanoma problem that seems to be herd specific. There is a possibility that goats can be used as an animal model because of this herd specific susceptibility to melanomas. It suggests there is some other factor, perhaps dietary, which is certainly worth investigating.