Designer animals made easy

March 27, 2002

A BIT of fly DNA might be about to turn the trickle of genetically modified animals into a flood. Biotech company Tosk of San Francisco says it can add genes to mammalian cells with unprecedented efficiency with the help of fruit fly DNA that can jump in and out of chromosomes.

The company's claims are being greeted with a mixture of enthusiasm and scepticism by other biologists, who warn its results have yet to be independently confirmed. "But if it works the way they claim, it's revolutionary," says Tom Rosenquist of Stony Brook University in New York.

Introducing genes into mammals is laborious and expensive at present, so the technique is only used for research and to create animals that yield high-value medical products. But if making GM mammals becomes cheap and easy, companies could soon be modifying everything from the farm animals that produce our food to our pets. Tosk's method could even be used to correct genetic faults in people.

At the moment, GM mammals are usually made by injecting naked DNA directly into an egg. But the success rate is extremely low: to get just one GM animal, a skilled technician has to carry out dozens of injections and then implant the resulting embryos. An alternative is to start with ordinary cells and then try to clone the few that integrate the extra DNA. But this isn't very efficient either.

Tosk's method cuts out this tedious manipulation, New Scientist has learned. The extra DNA is simply injected into an animal's bloodstream. Within a couple of weeks, it is integrated into a high proportion of cells in many different tissues, says Tosk's chief executive Patrick Fogarty. Since some sperm and egg cells are also altered, normal breeding can then produce animals in which every cell carries the extra DNA. When mice are modified by injecting DNA into their tails, Fogarty claims, 40 per cent of their offspring on average carry the extra DNA-an amazingly high proportion.

Tosk's secret is jumping genes, or transposons, which are found in many organisms. They are genetic parasites: bits of DNA with no function, merely the peculiar ability to spread themselves around by hopping in and out of DNA with the help of a "cut-and-paste" enzyme called a transposase. A typical transposon consists of a gene that codes for a transposase flanked by unique marker sequences. When the enzyme is produced, it homes in on the markers, snips out the entire transposon and pastes it elsewhere in the cell's genome.

One of the most active transposons is the P-element, found in fruit flies. For decades, scientists have used it to make transgenic flies by replacing the transposase gene with the genes they want to transfer. But nobody could get it to work well in mammals.

Now Fogarty, who left Stanford University to start Tosk, says that by tinkering with the structure of the P-element, his team can get it to integrate into up to 80 per cent of mouse and human cells in culture. The delivery system consists of two bits of DNA: one containing the gene to be introduced, flanked by the marker sequences, the other containing the gene for the P-element transposase.

Trillions of copies of these bits of DNA, encased in fatty globules that help them enter cells, are injected into an animal. The animal's cells then start producing the transposase, which cuts and pastes the extra gene into a random site in the cell's genome.

The transposase gene itself isn't integrated into cells' DNA, but breaks down after a couple of weeks. Once that has happened, the inserted bits of DNA stay put.

Tosk has just launched a service to make transgenic animals, and a few scientists have begun placing orders. "If it's true it's wonderful," says biologist Laurence Bugeon of Imperial College, London, who has just got a batch of mice from Tosk. Fogarty says they have also begun collaborations with about a dozen corporate partners that will test the technique in goats, cows and pigs. So far, however, no details of the company's experiments have been published, and it could be months before its claims can be independently verified. Other scientists say that the company needs to do more experiments to prove that gene integration is indeed happening through transposition.

Still, Tosk is not alone in developing transposons for gene delivery. Published work using other transposons suggests that the technique might also become a valuable tool for correcting genetic defects in people.

Right now, the main approaches in gene therapy research are to infuse naked DNA into cells or to use viruses to add DNA to the genome. But naked DNAsurvives only a short time, and there are obvious safety concerns with viruses. Transposons could provide the best of both worlds: stable integration without the dangers of viruses.

One transposon derived from fish, called Sleeping Beauty, has been used successfully to deliver genes to the livers of mice with haemophilia (New Scientist, 22 November 1997, p 11). But even in culture Sleeping Beauty integrates at a low rate-just 5 to 6 per cent of cells. Tosk says its transposon is about 10 times as efficient, an enormous difference.

Of course, there are major concerns that need to be addressed if transposons are ever to become tools for gene therapy. "But if you look at the general principles, it's a wonderful system," says Richard Mulligan of Harvard Medical School. "Time will tell."
-end-
Author: Sylvia Pagan Westphal, Boston

New Scientist issue 30 March 2002

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