The chemical reagent company Sigma-Aldrich is hoping to spin a new business out of genetically modified (GM) rats. Sigma Advanced Genetic Engineering Labs, based in St Louis, Missouri, should start taking orders for custom-made and off-the-shelf knockout rats as early as October, according to Sigma representatives. Among the first releases will be knockouts for the genes ApoE1, implicated in atherosclerosis and Alzheimer's disease, and Disc1, which may have a role in schizophrenia.
Such GM animals make up a significant segment — around US$700 million — of the multibillion-dollar market for lab animals and associated services, and that share is predicted to grow by 12% per year over the next 3 years, according to Eric Ostertag, founder of Transposagen Biopharmaceuticals in Lexington, Kentucky, which currently supplies the majority of the world's GM rats.
But for the moment, the GM animal market is unquestionably dominated by mice. In Britain last year, for example, they outnumbered GM rats by 1.2 million to 6,000. Although rats are deemed to be superior to mice as models for several human diseases, particularly disorders of the nervous system, rat genes are much more difficult to manipulate using embryonic stem cells — the approach commonly used to create mouse knockouts. Sigma-Aldrich, however, is using zinc finger nucleases — engineered fusions of DNA-binding and -cleavage proteins — to delete specific genes directly in the rat embryo. Sigma-Aldrich licensed the zinc finger nuclease technology from California-based Sangamo Biosciences for $13.5 million in 2007, and reported knockouts using the technology recently in Science1 together with collaborators at the Medical College of Wisconsin in Milwaukee.
David Smoller, president of the research biotech business unit at Sigma-Aldrich, says that the company has worked closely with customers to develop lines that should be popular. The firm plans to announce its first catalogue of animals, which should fetch $300–$500 each, in October at the Society for Neuroscience meeting in Chicago, Illinois. A breeding pair of made-to-order rats developed using the zinc finger technology should cost $80,000–$100,000. That's comparable to the costs of developing custom mice through traditional knockout technologies, says Smoller, but should in principle take only a third of the time.
Money spinner?
The zinc finger protein technology, owned by Sangamo and licensed exclusively to Sigma-Aldrich, has had the research community salivating for several years owing to its precision and flexibility. Michael Wiles from The Jackson Laboratory — a non-profit research organization based in Bar Harbor, Maine, which develops and distributes mutant and inbred mice — says that the community has been waiting to see what zinc fingers can do for research, but also how the licensing will pan out. Restrictive licences could hamper the sharing of newly created rats for academic work, and may limit their popularity, he says: "I think one can argue fairly strongly that by allowing academics to develop the systems they will prosper far more than if it's restrictive."
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Transposagen — which creates genetically modified rats using transposons, or jumping genes that insert themselves randomly throughout the genome — regularly works with the research community to characterize its creations. In part to foster this collaborative development, they provide their rats to academics "at or near cost" according to Ostertag. "We don't plan on making money off the academic market," he says, but he hopes to sell useful models to pharmaceutical companies and biotechnology firms.
Sigma-Aldrich is targeting what they hope will be high-value models. "Sigma's goal is to make technology broadly accessible," says Smoller, pointing out that licensing fees and rules will apply across the board as they do for other reagents. "We're not trying to change that paradigm."
Wiles says that picking the right strains will be crucial if the company is to make a profit. "There are a few big sellers from our genetically engineered lines," he says, "but most are money losers — a service to the community."
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References
- et al., Science 325, 433 (2009).