The debate is raging over whether genetically altered animals can be patented, Aisling Irwin reports. It is small and furry and designed to develop cancer. It is the oncomouse and it is unaware, although perhaps not blissfully so, that it is the source of heated arguments between lawyers, campaigners and administrators across Europe over whether it can be classified as an invention, and whether anyone can claim to "own" it. It is also unaware that a hearing aimed at ending this dispute, held by the European Patent Office recently, ran out of time and was left unresolved.

Thus the oncomouse, (a real mouse into which a cancer gene has been inserted), is still the subject of a patent held by Harvard University. Who knows when the appeal lawyers will make their decision?

But there is confusion about what the EPO is trying to decide. This is not a decision about whether people should manufacture transgenic animals. They are already produced, hundreds of thousands of them: animals with genes deleted so that scientists can see what they code for; animals manipulated to develop human diseases; animals that produce unusual substances in their urine or milk which may be of use to humans; and farm animals manipulated to grow fat quickly.

Although they are all transgenic, these animals differ widely in the extent to which they suffer. What they have in common is that their numbers are increasing. It is not at all certain that refusing patents will halt this increase - nor that granting patents will accelerate it.

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Numbers in the United Kingdom are small at present. The Home Office monitors them. In 1994 184,000 procedures were performed on transgenic animals. A further 202,000 procedures were performed on animals selectively bred to have harmful genetic defects. Selective breeding is done by choosing animals that naturally have a certain characteristic, such as muscular dystrophy, and breeding them with each other to concentrate the defect in the next generation. Transgenic animals have their DNA deliberately altered when they are fertilised eggs. But the number of transgenic animals running around in the UK may be less than 184,000 - since producing a transgenic animal counts as one procedure and experimenting on it afterwards counts as another.

By contrast, there are only 300 transgenic animal patent applications waiting for approval at the EPO, stuck there until a decision is made about the oncomouse. Many of these applications originate from the UK but the EPO claims it is unable to tell how many.

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Perhaps the most flamboyant transgenic animals in the UK are Tracy the sheep and Astrid the pig. Both are the subject of patent applications.

Tracy is an example of the most benign form of transgenic animal. She produces a protein in her milk which can be used to treat emphysema in humans. She is owned by Pharmaceutical Proteins, a company founded in 1987 to commercialise work done by the Roslin Institute in Edinburgh. Ron James, managing director, says he has four or five flocks of sheep each producing different proteins. The company is also investigating production in mice, rabbits and cows. Tracy's product, the most advanced, should complete clinical trials and arrive on the market in a few years.

Barring technological hitches, there could be a modest increase in the number of Tracy-type animals over the next few years, according to James: "There could be 20-30 proteins being produced ultimately, each one by a flock which could number anything from ten to thousands." Some animals would be manufactured only temporarily, for example to produce monoclonal antibodies which can prevent the rejection of an organ after a transplant. Production of the antibodies would then move to the laboratory.

Astrid the pig was bred in 1992, by Imutran, which filed a patent relating to her. She is said to be the first ever transgenic pig. Imutran's aim is to rear pigs with organs that can be transplanted into humans.

There were 619 procedures registered in 1994 for transgenic ungulates (ie hoofed mammals, including sheep, horses, pigs, cows and goats). James points out that all offspring of transgenic animals are included in the figures. Some are bred for disease resistance. The two British patents have been awarded for sheep that grow extra wool and sheep with enhanced growth rate. Engineering to produce more meat is a major goal. David King, editor of Genethics News, says: "In the mid-1980s the trend was to use growth hormone genes. This proved a disaster. The animals had major health problems." Nevertheless the quest goes on.

Probably these latter, commercially motivated manipulations stand at one end of a public acceptability scale and those that produce disease-preventing proteins in their milk at the other.

But most scientific and medical procedures are carried out on mice. 181,000 on transgenic mice in 1994; 2,000 on rats. (These, of course, are additional to the 202,000 experiments on animals selectively bred with harmful genetic defects). Nicholas Wright, director of clinical research at the Imperial Cancer Research Fund, says: "We're making transgenic animals all the time. They are an invaluable aid."

Many of these mice are used as models of disease. "They are now a standard tool in genetic research," says King. "Most genetic departments in universities will be making them." When scientists announce they have discovered the gene for a disease, it is likely that the next step will be to insert that gene into a mouse embryo to see what happens to the resulting mouse. If the mouse proves to be an accurate model of the disease then scientists can test their gene therapy experiments on it before transferring the trials to humans.

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This process has gone furthest with cystic fibrosis. Myc Wriggulsford, director of the Research for Health Charities Group, which defends animal experiments on behalf of medical research charities, says: "There was a big worry that while trying to insert genes into lung tissue in humans they might cause lung cancer. After six months of experiments on mice they got permission to insert genes into humans."

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Critics of such work have observed that gene therapy has so far achieved almost nothing. The researchers reply that it is early days. John Bishop, of Edinburgh University also observes: "The likely cost of any such therapy, in a society in which we turn people off kidney machines on a cost basis, is enormous. It's unlikely that there would be any general application of this therapy."

Another approach is to "knock out" a gene in the embryo and work out what that gene does by looking at the state of the mouse when it is born. This, say scientists, has advanced understanding of the genetic contribution to cancer.

Scientists also say that transgenic animals have enabled great leaps forward in the understanding of prion diseases, such as scrapie and mad cow disease.

Wriggulsford claims that these disease models account for almost all of the mice and rat figures but there are other uses, which have a less direct relationship to the prevention of disease. You can knock out a gene with a neurobiological function and see how a mouse's behaviour, learning or memory are affected. You can alter genes that affect the embryo's early development. These are the two most important areas for basic science research on transgenic animals because there is no way that they can ever be studied using animal alternatives such as cell cultures, says Professor Bishop: "The fundamental research is going to be immensely valuable for understanding almost any physiology of the body properly."

The people who object to transgenic animals claim that they are not nearly as useful to research as scientists hope they will be. But, even if they were useful, the objectors would still condemn their production on ethical grounds. Donal Crawford of the British Union for the Abolition of Vivisection says: "It causes pain and suffering to a large number of animals. We believe that the insertion of genes from other species into lab animals is an ethical minefield. The directions in which that approach to life can lead opens up a Pandora's box."

But Nick Hastie, head of the MRC Human Genetics Unit at the Western General Hospital in Edinburgh, describes such experimentation as "a necessary evil for progress in understanding human biology".

Most research funders and scientists who will talk about transgenic animals predict that their production will increase. When the 1994 figures for scientific procedures on animals came out about six weeks ago, they showed a surge, only the second after 17 years of declining numbers. Mark Matfield, of the Research Defence Society, attributed the increase to transgenic animals and predicted that numbers would no longer go down. Wriggulsford says: "It is probable that we will have a huge increase in the number of genetically engineered mice. There's an explosion in the understanding of which genes are causing which diseases."

Major research funders, such as the MRC, already have centres which produce transgenic animals for wider use. In the US there are commercial companies selling transgenic animals. At least one academic centre in the UK makes mice to order for academic and commercial customers, and charges for them. Others send them for free.

Less certain that there will be a huge increase in the number of transgenic animals being produced is the Cancer Research Campaign, whose animal research figures have dropped dramatically after strenuous efforts at reduction. CRC scientific director Gordon McVie says that while his institutes are increasingly reporting that the principal use of animals is now transgenic, they are only used in small numbers.

Campaigners against the patenting of transgenic animals claim that patenting will give a massive boost to the industry because of commercial opportunities. Yet many patent applications have lapsed. The Medical Research Council had applied for a patent for a Cystic Fibrosis mouse. "Having established a licencing deal with companies we decided we couldn't justify the cost of holding the patent," said the MRC. The mice are very difficult to breed so it does not expect to lose out because of this.

The British Technology Group and CRC-Technology, the technology transfer arm of the Cancer Research Campaign and the Wellcome Trust have also let patents lapse. The Wellcome Trust was unable to provide someone to comment on transgenic animals. CRC-T says: "It has been our policy since the beginning of the year not to patent transgenic animals after consideration of moral, scientific and utility issues."

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But perhaps the surge in numbers of transgenic animals will last only a decade or two, with the long-term trend firmly in the direction of reducing experimentation on animals to a bare minimum. Professor Hastie says: "It could be that in ten or 20 years time we have enough of an understanding of what these genes do for transgenic animal experimentation no longer to be necessary."