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An ophthalmologic tour-de-force

Elizabeth Engle, MD, never expected to land in her specialized research niche. But deep curiosity and a single patient encounter led her to become the world's primary researcher probing the genetics of strabismus, or misalignment of the eyes.

Her work, blending genetics with neuroscience, has defined a new category of congenital disorders that leave children unable to move their eyes in specific directions. These conditions impair vision and are often socially isolating—the eyes are fixed in abnormal positions, forcing children to hold their heads in odd positions just to see properly.

Although Engle attended an academically limited high school in a "somewhat decaying" neighborhood of Columbus, Ohio, she had an excellent biology teacher who emphasized hands-on science, which Engle loved. In college, she became fascinated by genetics, and in medical school, found herself drawn to neuroanatomy.

In 1992, as a neurology resident at Children's Hospital Boston, Engle met a little boy with droopy eyelids whose gaze was frozen downward. His father, a cousin and a cousin's daughter had a similar condition. New tools had recently emerged in genetics, and Engle wondered if discovering the mutated gene behind the toddler's disorder might explain how he lost his eye control. Over tea one night in the family's home, she learned of another branch of the family with the condition and got permission to contact them. "Late at night is sometimes when you're told stuff that moves your research forward," Engle says.
With enough family samples to do genetic studies, Engle realized she needed to make a foray into laboratory research. "I thought there was no way that I could ever run a lab," she recalls. "I didn't have a PhD and was never officially trained in the lab. I didn't even know how to make chemical solutions."

Nonetheless, Engle talked her way into a research fellowship in Children's Department of Genetics with Louis Kunkel, PhD, and Alan Beggs, PhD. Aided by their mentorship and resources, she identified the location of the gene mutated in the boy's disorder, then defined its neuropathology by conducting an autopsy of an affected family member. Eventually, she traced the boy's disorder to a single amino acid change in a protein called KIF21A, whose job is to carry specific cargo to growing nerve fibers. The subtle change apparently left the cargo stranded—and left two of the boy's eye muscles without cranial nerve stimulation. Modeling the disorder —congenital fibrosis of the extraocular muscles type 1—in mice, Engle's lab is now studying exactly how the mutations disrupt KIF21A's function, and exactly what its cargo is.

Since that first case, Engle has searched for other families with unusual congenital eye-movement disorders, gaining their trust and building a database of more than 1,500 patients, large enough to pinpoint many rare genetic defects. She makes fewer road trips now, but instead has developed a network of collaborators, allowing her lab to pool cases from all over the world. To date, she's discovered six different forms of strabismus arising from a variety of genetic errors in brainstem motor neuron development.

Engle heads a National Eye Institute-designated strabismus diagnostics center at Children's. As a Howard Hughes Medical Institute investigator, she now receives steady financial support that she hopes will help her expand her research and, eventually, translate her discoveries into therapies.

"Sometimes I question dedicating an entire career to these rare disorders," Engle admits. "But each affected individual is so grateful for our work, and each disorder is itself fascinating."

Complex eye-movement disorders also make an ideal model for understanding more common central-nervous-system problems. While the brain contains millions of neurons, making mishaps difficult to identify, the eyes are relatively simple. Just six muscles move the eyeball, controlled by just three sets of cranial nerves, so the number of places things can go wrong is relatively finite.

"Think of the U.S. railroad system," Engle says. "Penn Station, with many trains and switches, is hugely complicated compared to a small Midwestern town with a single train going through daily. Yet understanding how that one train and switch work could help in figuring out Penn Station's complexities."

The laboratory life turns out to suit Engle well. "I'm much happier if I have protected time to focus deeply on a narrow topic," she says. "I love caring for patients, but I found it difficult to do anything else intellectual if I knew my pager could go off at any moment. I don't necessarily have as many daily satisfactions in the lab as I would taking care of patients, but I'm one who does well working toward long-term goals."