In her lab at Princeton, Rebecca Burdine keeps a number of zebrafish with odd mutations. One of the most striking is “curly,” a mutation so severe it bends the fish’s spine into a permanent C. It looks like an extreme case of scoliosis–a sideways curvature of the spine–most common in teenage girls.
Burdine, a developmental biologist, was studying congenital heart defects, not scoliosis, when she asked an undergraduate in her lab to grow curly zebrafish. It did not go well. “She would say things to me like, ‘I don’t have mutants today,’ and I’d say, ‘But that makes no sense,'” recalls Burdine. It turned out something else was odd about the curly mutation: It was temperature sensitive. The warmer the water, the more fish grew curved spines. “We didn’t realize until later that she put them at different temperatures depending on her class schedule,” says Burdine.
Ten years later, that accidental discovery has enabled a study, published in Science, that adds evidence to an intriguing new genetic cause for scoliosis. It’s related, actually, to the congenital heart defects that Burdine was originally studying. What ties the two problems together are cilia, slender hair-like structures that project from cells.
It’s easy to take for granted that our spines grow straight, our hearts on the left, and our limbs in pairs. But it actually takes incredible coordination. Every cell needs to know where it is so that, for example, the cells in your feet don’t grow into an eyeball. In a developing embryo, cilia consistently beat fluid in a single direction that becomes “left,” so the heart grows on the left side of the body.
Cilia inside the spine also move cerebrospinal fluid, bathing the spinal cord and brain. “The spine spends a lot of time trying to sense what’s going on in other parts of the body,” says Burdine. Disrupt the regular flow of that cerebrospinal fluid–in the case of a tumor that blocks the fluid or defective cilia that can’t beat properly–and the spine begins to curve.
Burdine and her colleagues figured out that their curly zebrafish had defective cilia. To prove that defective cilia then led to curved spines, they made use of the curly mutation’s temperature-sensitive quirk. The team raised curly zebrafish at a cool temperature for 19 days and transferred them to warmer tanks until the fish’s spines began to curve. Staying in warmer tanks made their spines more and more curved. Putting them back in the cool tank stopped it from getting worse.
The team checked out four other cilia-related mutations, and found they also caused the zebrafish’s spine to curve. Last year, a team in Canada and France found a different mutation in families with unusually high rates of scoliosis that affected cilia. When that team put their mutation into zebrafish, it also caused the spine to deform. “There is no one gene, one scoliosis,” says Florina Moldovan, a spinal deformities researcher at the CHU Sainte-Justine, who worked on that study. But together, these cilia mutations might explain some of the scoliosis cases doctors currently term “idiopathic,” official medical jargon for “we have no idea why this happens.”
Scientists still have to learn how exactly the spine senses cerebrospinal fluid flow. Having the zebrafish as a good model for scoliosis is a huge step, though. Mice, a more common lab animal, aren’t good for studying scoliosis because they walk on all four feet, which stabilizes the spine. “No one’s reported much scoliosis in mice,” says Christina Gurnett, a neurologist at Washington University in St. Louis. So giving mice scoliosis means taking pretty drastic measures, like amputating two legs to force them on their hind feet.
Other mysteries, like why scoliosis mostly afflicts teenage girls, still remain. “With scoliosis, we’re not in the dark ages, but we’re catching up to a lot of other disorders,” says Gurnett. Defective cilia may explain only some cases of scoliosis, but the theory is at least chipping away at the maddening label of “idiopathic.”