How do biologists choose the animal model or lab samples they will spend so many hours studying? Some researchers start with a problem that they find intriguing and then look for suitable models, while others become enamored of a particular organism and use it exclusively. David Kingsley, an HHMI investigator at Stanford University, was always fascinated by how organisms develop and by evolution, but he also wanted to make sure his work would be directly relevant to human disease. So he decided to focus on something "unique to vertebrates"—vertebrae, the bones of the spinal column. And he chose to study skeletons.

The mouse was the obvious place to start. Looking through a mouse genome map in 1990, Kingsley put a red dot over each place where a genetic trait that affected some aspect of skeletal development had been mapped to a mouse chromosome. He recalls that "there were 150 different mouse genes that affect, or disrupt, various aspects of building the skeleton. They affect bone formation, bone repair, how many bones you have in your finger, how well you can replace bone fractures, whether you get arthritis, what your tail or vertebral column looks like—tons of different skeletal traits."

His research team then went through that collection systematically to try to isolate genes that control key steps in skeletal development. "It was almost a five-year project at that time to pick one red dot and say, 'This looks like a really interesting gene. It maps to this region of a chromosome. Let's try to isolate all of the DNA that's in that region of the chromosome, decode all the genetic information that's in there, and find the gene that's responsible for this particular trait,'" Kingsley recalls. "The genome project is dramatically shortening the time it takes to find such genes and their pathways."

Working with mice in this collection, Kingsley's team was able to identify genes that control where and when bones form in the skeleton, as well as where joints form between various skeletal elements.

The team also studied skeletal diseases. "Some of the old classical mouse mutations control traits like arthritis," Kinglsey says. "We have recently isolated one of these genes and shown it encodes a completely novel protein that controls mineral deposition in joints. This gene is highly conserved in vertebrates, but it's not in the worm or fly databases, and we haven't been able to find a copy of it in any invertebrate." Not everything is conserved across different animals, Kinglsey points out. "We wouldn't have identified this gene without studying vertebrates themselves."

As his work proceeded, however, Kingsley began to marvel not only at the large number of similarities between the basic skeletal structures of various kinds of vertebrates but also at the structures' diversity. His lab is filled with animal skeletons of differing sizes and shapes.

"Look at all these different animals," he says, pointing to the skeletons of a rat, an armadillo, a chicken, a pigeon, a frog, and a salamander. "They are all made of the same cartilage and bone, but each organism is able to take that tissue and mold it into a different shape to produce an organism that is adapted to a particular function.

"If you want to make an organism that can fly, like a bat, you have to take what used to be hands and somehow stretch out all of the fingers in just the forelimbs—not the hindlimbs, because you still want a traditional grasping foot down there—to form a skeletal structure that can support an adaptation to flight. If you want to make an organism that can swim, look at a seal: it has many more bones in the hindlimbs in order to produce a flat, flipper-like structure that serves to paddle the water. If you want to make an animal that can run fast, you get rid of lots of bones. You don't want all this stuff flapping around; you want a couple of long things that you can run on efficiently.

"So the limbs of a bat, a seal, and a horse look very different from each other. And we still have no idea what types of genes and molecular changes are responsible for these dramatic differences." Normally, when geneticists want to understand the basis of differences between two organisms, they cross the organisms and map the genes that are responsible for the corresponding traits in their offspring, Kingsley explains. Unless the two organisms belong to the same species, however, they produce no offspring.

"Crossing a bat and a horse is not something we're stupid enough to try," he says. "But conceptually, that's the kind of thing we'd like to do. So we tried to think of a realistic way of doing crosses between species that have different skeletal shapes."

— Maya Pines

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Vertebrates of all kinds fascinate David Kingsley...

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