The Strange Story of the Lab Mouse Bred to Die
The "Oncomouse" was developed to help scientists cure cancer. The catch is that it develops breast cancer six months into its existence.
A mouse. Photo: Antje Schulte / Alamy Stock Photo
Ever since the dawn of time, man has yearned to give mice cancer.
But it wasn't until the mid-1980s that we finally became the godlike tumour-chuckers of our collective imagination. Enter the Oncomouse (US Patent number 5,925,803), the second organism ever to be copyrighted, and the first mammal. The Oncomouse is born, is suckled by its mother, starts to contemplate its rodential place in the universe, then, like clockwork, develops breast cancer around the sixth week of life.
It is, scientists will tell you, a consistent product. That's the genius of it. Not that it gets cancer; you can bombard any old mouse with any old radiation any time you like if you fancy it, and it will genially start sprouting melanomas. The point is that it gets the same cancer, the same way, without too much other stuff going on. Cancer is pretty much the only thing wrong with it – so you can compare your experiments with those of others.
This is a mouse so sophisticated that it comes with an End User Agreement, like software, a long checklist of best practices, special injunctions.
"I was working in a lab," explains one London-based mouse user. "And my supervisor was called away on business, so we couldn't do the experiments we'd planned, which meant that I had to go around and kill all of the mice in their sixth week, because that was what it specified in the contract."
Scientists are very strict about on their animal ethics protocols. "A lot of this stuff is highly competitive," says the same source, who asked to remain anonymous. "If a rival biotech firm can show you've mishandled your stock, just the taint from that could sink the billion-dollar drug you're developing."
The alternative name for the Oncomouse is the "Harvard Mouse", because it was invented by two Harvard University rodent-interferers – Philip Leder and Timothy Stewart – in 1984. The pair had figured out a way to knock a certain strand of mouse DNA out and replace it with a cancer gene, by injecting mouse eggs with a specially-made virus. They inbred the resulting creature, recycling it by breeding first-cousins in a consistent pattern that meant – for all intents – you were getting the same mouse born over and over again.
To slightly over-simplify, after the egg virus-insertion phase, you breed granddads with their granddaughters, grandmas likewise, in a specific pattern that means your breeding population is recycled evenly. Over time, that means you have a stable set of the genes you want. "Imagine it like a sine wave," our mouse user explains. "You start with a pattern that's quite jagged, but over time, you're recycling the same elements, so it smoothes out." And yes, that does mean you up the number of defective mice born within your population with the same sine wave regularity. "Unfortunately," says the mouse user, "you have to kill those ones."
Unfortunately for Leder and Stewart, their research had been sponsored by US Pharmaceuticals giant DuPont, which now saw an easy way to earn back their investment and then some. They patented the Oncomouse, and marketed it aggressively. There were T-shirts.
The Oncomouse was a disruptor. It overturned our ideas about what a patent even was, and in the process put a lot of scientists' noses out of joint. Whereas before, lab mice were effectively party favours, traded between labs within the small, tight-knit experimental community, now, you had to pay a hefty charge per unit to DuPont. You weren't allowed to breed them. Plus, DuPont not only wanted oversight on your projects, they taxed you for a share of any commercial breakthroughs made using their product.
The controversy boiled on for years. North of the border, the Canadian patent office rejected the very idea of any animal patent outright because "it was not what the Patent Act originators had intended". In the EU, in 1991, the authorities eventually ruled that it was possible to patent it, but only after an appeal court distinguished that animal varieties were excluded from patents, while animals were not.
All of this philosophising gradually became more and more irrelevant. In 1999, DuPont began to allow non-commercial breeding of their mice. By 2012, it was reported that the final patents had lapsed. These days, Oncomice are essentially a generic you can buy from anyone, but DuPont still owns the copyright on the name.
In the meantime, technology had been overtaking DuPont anyway. In 1989, three British and American scientists developed a mass-market technique: the Knockout Mouse. Now, you could take any part of the rodent genome, remove it, substitute in another bit and get a mouse that was fat, or that had no immune system, or maybe it just looked at you a bit funny. A mouse that is, actually, a rat; a rat that can get diabetes on command: the "BBDP" Rat.
By 1993, this wave had even led to a backwards-Oncomouse. Rather than insert a cancer-promoting gene, you turned it into a double-negative, flipping off the p53 gene which allows mammals to zap their own tumours before they grow: voila – big grey greasy lumps of the stuff.
There are now several thousand varieties of knockout mouse out there, and the market is competitive: a quick google pulls up a slew of sponsored ads: "Fast Turnaround. Custom Mice Models 100% Money Back Guarantee. The More You Order, The More You Save!" Around $20,000 (£15,670) will get you a founder colony of rodents with any reasonable switch flipped.
But the same question that applies to all animal testing applies especially to the genetically modified ones: are they a good enough model? Take dementia. Millions have been pumped into potential cures that might work at the mouse trial level, but fail when applied to humans. Mice develop the same plaques in their brains that cause dementia, but then do not display the memory problems seen in people.
That's why, in the past year, researchers have begun talking about a sort of Oncomouse-squared. Revise the mouse so that it not only gets dementia, but so that its brain structures also more closely resemble those of humans. In the future, re-mapping mice bodies towards human ones could become its own specialty.
Not everything that is possible is permissible, mind. In 1992, Upjohn Pharmaceuticals invented a knockout mouse that mimicked male pattern baldness – the hair follicles becoming smaller and smaller until they disappeared. But the ethics boards rejected the Upjohn Mouse because they judged that the harm to the mouse was greater than the potential benefit to humans – surely an insult to the struggles of bald men everywhere.
No such luck for the Oncomouse. In his little Groundhog Day life, this immortal inbred just can't shake that iffy feeling that, any minute now, for some reason he can't quite fathom, he’ll discover blood in his stool.