A legal battle over a genetically modified rodent is putting the lucrative mutant mouse industry under the microscope
James Meek
In October a jury in San Francisco will make a decision in one of the new millennium’s most bizarre and complex court cases. Teams of elite lawyers will have spent weeks studying and arguing over crates of laboratory notes, letters and e-mails, prised from the reluctant hands of some of the United States’s leading medical researchers. The case is a landmark battle between the public and the private sector; between a rapidly growing Dublin-based pharmaceutical firm, Elan, and an influential non-profit medical research organisation, the Mayo Foundation. At stake in this epic struggle: who owns a mouse.
Few people have heard of mouse TG2576. But the mouse and its descendants are mighty mice. Pound for pound, they are probably the most expensive animals in the world: a breeding trio of males is said to be worth up to $1-million. TG2576, also known as the Hsiao Mouse after its creator, Karen Hsiao-Ashe, is precious because it is demented. It is born to contract Alzheimer’s disease. Dr Hsiao-Ashe, of the University of Minnesota, designed it that way.
It is known as a “transgenic” mouse. Its genes, and thus the genes of its offspring, are artificially altered so that its cells produce a mutant human protein that has been implicated in Alzheimer’s disease. When the mice are 10 months old they begin, reliably, to get senile. They forget things they were just taught. A mouse with Alzheimer’s is a gateway to beating the illness. That makes it valuable to the millions of Alzheimer’s sufferers around the world, to the researchers trying to find a cure, and to the shareholders of companies trying to get cures to market.
The Minnesota-based Mayo Foundation, which provides Hsiao mice at cost to academic researchers around the world, and sells them to commercial companies, won’t say how much the private sector is prepared to pay for the rodents. But Mayo neuroscientist Steven Younkin, one of Hsaio’s collaborators, says: “Let’s take a figure of, say, $2-million. Do you think any firm working seriously on a treatment with a potential annual market of $150- billion is going to stop for $2-million? It’s a drop in the bucket.”
One of those firms is Elan. Its share price has shot up since it began trials of a vaccine that may prevent or treat Alzheimer’s. The vaccine was developed with the help of another, secret strain of Alzheimer’s mouse that Elan created. Unlike the Hsiao mouse, Elan’s mouse is not for sale. But keeping its mouse under lock and key is not enough for Elan: it wants to prevent distribution of the Hsiao mouse as well, accusing Mayo of infringing its patents on a third strain of mouse. Hence the court battle.
Elan refuses to say what its ultimate goal is in suing Mayo. Younkin is more forthcoming. Like other US researchers, he has been ordered to make research notes and data available for the case. (One indignant colleague says he would rather go to prison than surrender his notes.)
“I think [Elan’s] strategy is, ‘Let’s make sure we make all the money we possibly can, and if it slows down research, that’s too bad. We’ve got our shareholders to worry about,'” says Younkin.
Mice have never been so big. The world of medical research is agog at the wondrous possibilities for miracle cures and extended lifespans offered by the great project to decipher the three billion- letter human genetic code – the Human Genome Project. On the outside, it is a work of robotics and computers, of dizzyingly powerful microscopes and cell manipulation machinery. On the inside, it’s about mice. The machines churn out the genes; only the mice, whose genetic make-up is humblingly similar to ours, can tell us what the genes do.
“At conferences people are swapping their mice around, arranging marriages between mice,” says Dr Denis Alexander, who has helped design mice to investigate the human immune system at the Babraham Institute outside Cambridge in England.
“You can’t even measure how much slower research would be if it wasn’t for the transgenic mice. The genome project would be throwing out all these genes and you wouldn’t be able to do experiments. To do it the traditional way, you’d be talking about hundreds of years of work. If we didn’t have these mice we’d still be in the immunological Dark Ages.”
The mice are not as nature made them, but mice as scientists fabricated them. In the early days of patent mice there were mutant mice: researchers would bombard hordes of mice with radiation or put special chemicals in their drinking water, pick out chance mutations that seemed interesting and breed the mutants. This was how the Obese Mouse, the Diabetic Mouse and the Muscular Dystrophy Mouse were produced. Others, such as the Nude Mouse, were made by simple inbreeding. Then, from the 1980s onwards, came transgenic mice – mice with genes added, usually human genes – and knockout mice, which have genes taken away to see what will happen.
The total number of man-made mice strains is impossible to calculate because many firms have made mice in secret. But one guess is between 2 000 and 3 000, with new mice being announced every week, all mimicking some human flaw. There are Huntington’s disease mice and cystic fibrosis mice, mice that get cancer, mice with bad hearts, diabetic mice and asthmatic mice.
In 1997 US scientists produced a “Schwarzenegger” knockout mouse with two to three times normal muscle mass. Another supermouse was kitted out with a human gene that made it resistant to heart disease. Last year Italian scientists announced a knockout mouse that lived up to a third longer than conventional mice; in the US, the Mahogany Mouse ate and ate, but stayed thin.
Other knockout mice – neurotic mice, mice susceptible to cocaine addiction – have led researchers to make contested claims about the relationship between mental states and genes. Faith in the mouse as model for human frailties is extraordinarily strong among scientists. If there were to be a common epitaph on the graves of biotech companies whose bold new treatments for people failed, it would be: “It worked on mice.” Yet there is a powerful feeling in some research camps that the long-awaited pay-off for sick humans is on the horizon, and these rodents are to be thanked.
“The mice they’ve made are the most important advances in disease research to have been made in recent years,” says Dr Simon Lovestone, a British Alzheimer’s researcher. “It’s no exaggeration to say drugs will be made that will actually treat this disease within five or 10 years.”
Figures from the British Home Office, which keeps records on every mouse that passes through British laboratories, tell the story. Since 1977, when 3,3-million scientific “procedures” on mice were carried out, the number has dropped to 1,6-million. But in the 1990s the number of procedures on transgenic and knockout mice soared, from 48 000 in 1990 to nearly half-a-million in 1998.
Scientists can get mouse embryos or full-grown mice by post; they can even order them over the Internet. “You can just go through the Web, make a request for a particular mouse strain, and we will send it off to you,” says Professor Steve Brown, of the Medical Research Council’s big mouse house at Harwell in Oxfordshire. His speciality is deaf mice.
Researchers love tailor-made mice.
Because their natural lifespans are short, the effects of their altered genes show up early. They breed quickly. They don’t take up much space. And scientists don’t get as much flak from animal rights campaigners and anti-vivisectionists for using them. They’re more like people than flies or worms are, but not as genetically close to us as monkeys, or as emotionally close as dogs.
Besides, research teams have powerful allies – the human sufferers from disease. The public has always been more ready to accept animal suffering to alleviate human suffering than to entertain hunters and gourmands, or to test cosmetics.
At the Babraham Institute Dr Alexander rarely sees his mice; genetically modified to have a failed immune system, they are kept in an airtight, windowless, germ-free world. No one can have access to them without stripping, showering, shampooing and going through an airlock. “They are very well looked after. I call it mouse paradise myself,” he says. “They get fed, watered, looked after, the temperature is controlled, and there are no cats. What more could a mouse want?”
Dr Lovestone, who used to work with mice, says: “Sometimes you have this cognitive distance. You look after the mice fabulously carefully, and then you come home and spread poison around to try to get rid of mice from your own house.”