Designing a Mightier Mouse

Posted on Categories Discover Magazine

Another issue: Most scientists aren’t experts in mouse biology.

“I think in the past, some investigators worked in a vacuum,” says Elizabeth Bryda, director of the Rat Resource and Research Center (RRRC). Scientists aren’t always thinking about the genetic differences between mice and humans because they’re focused elsewhere. “Maybe the species you’re working with isn’t the best species for the question, but you don’t know enough about the physiology or the genetics to recognize that,” she says.

Like mice, rats are common in labs. The two have minor physiological differences and, more notably, psychological variations that affect how they interact. But the issues plaguing mouse research often appear in rats, too.

RRRC helps solve that by acting as a kind of rat customization shop. Want a rat with pulmonary hypertension and a deficiency of serotonin? They’ve got the model for you. Or maybe one with cataracts? No problem. Thanks to CRISPR gene-editing tools, researchers can tweak the rat genome to create so-called transgenic animals with human-like disease traits.

Using gene editing to create rodents that are ideal research models could narrow the genetic divide between humans and their animal stand-ins. But scientists are still unraveling what makes a mouse tick.

To this end, the International Mouse Phenotyping Consortium is doubling down on the mouse and picking through its genome with the finest of combs. Mice have around 20,000 genes that bear strong similarities to humans. We know the function of about half of these, says Kent Lloyd, who directs the Mouse Biology Program at the University of California, Davis.

He and his colleagues at the consortium want to understand the other half. The process is painstaking and involves the systematic “knockout” — removal — of relevant genes in stem cell cultures. Once a gene is gone, researchers grow mice from the stem cells to see what happens. By 2020, the group hopes to fully understand the 20,000-gene bridge between us and our lab experiments.

Some efforts, like Austin’s NCATS, have stopped chasing the perfect mouse entirely. They’re developing computer models that can re-create human cells and organs to test how virtual humans respond to new drugs. Other researchers are building what some call “organs on a chip.” Introducing new drugs to plastic microchips lined with human cells should let researchers watch what happens without ever involving a living creature.

Scientists’ long relationship with lab mice has been one of incremental advances to improve a flawed system. Fittingly, this is exactly how most scientific research progresses — by critically examining what we know to expand our knowledge of what we don’t.

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