Dr. Bruce Appel ‘fishes’ for breakthroughs

Caregivers / Researcher

dr appel

Consider the lowly zebrafish. Throughout its development from embryo to hatchling — a mere 72 hours — it’s so slight that it’s clear, its tiny heart and spinal cord plainly visible through its glassy tissue. Fully grown, it’s barely the length of a pinky finger.

To aquarium snobs, the zebrafish is an entry-level species: cheap and hardy, but drab and boring. To developmental biologists like Dr. Bruce Appel, though, the zebrafish is thrilling: Prolific. Transparent. Illuminating. In Appel’s lab on the Anschutz Medical Campus, the zebrafish is literally shedding light on how the nervous system works and how it can go awry.

As one of Children’s Hospital Colorado’s trailblazing researchers, Appel studies axons, the wiring that connects brain neurons and motor neurons to muscles. His specific focus is myelin, the white sheath that wraps axons the way insulation wraps electrical wires. Myelination, the sheath-wrapping process, is crucial to brain development and learning, especially during early childhood development.

“You don’t form new axons after about age 8,” Appel notes, “but if you learn a new skill — juggling, playing the guitar — you create new myelin. New connections in the brain.”
Conversely, a lack or loss of myelin can interfere with brain or motor function, as in multiple sclerosis. 

Appel’s technique for studying myelination sounds like something out of a science fiction movie. Using zebrafish DNA that’s been modified by inserting a sequence from bioluminescent jellyfish and corals, he tinkers with genes associated with myelination, adding or removing bits to observe the effect. Then comes the Hollywood-worthy reveal.

“Shine a laser light on the animals you’ve modified,” Appel says, “and the myelin sheath around the axons glows.”

No sheath, no glow; it’s simple yet astonishing. Given the zebrafish’s prodigious fertility (females produce 500 eggs per week) and warp-speed development (the brain and spinal cord start developing just nine hours after fertilization), the team can test and observe the effects of many, many variables, seeing which ones torpedo myelination and which ones encourage it.

For Appel, who’s been studying zebrafish for more than a decade, myelination is the Great Frontier, the key to scientific mysteries and breakthroughs in neuroscience.

“Many of the big-ticket brain disorders — schizophrenia, autism, bipolar disorder — are ‘white-matter’ disorders, myelin disorders,” he says. “If we can figure out the activity code for wrapping axons, we can start figuring out how to fix problems.”

And that could be a game changer for children facing debilitating neurological diseases.

It’s a long way from the aquarium to the clinic, but at the end of that lengthy tunnel, Appel definitely sees it: the light, bright and beckoning.

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