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Three years later, in the last year of her neurology residency, Engle was forging ahead with her plan to learn genetics by studying the toddler's disorder, specifically called congenital fibrosis of the extraocular muscles (CFEOM) type 1. For help, she approached Beggs—a colleague at Children's Hospital studying muscular dystrophy with former HHMI investigator Louis Kunkel.
"She literally walked up to me in the quad one day with this proposal," says Beggs. "I was quite taken aback."
In muscular dystrophy, the eye muscles are spared from the progressive muscle weakening that affects the rest of the body. So Engle presented her idea to study CFEOM type 1 to Beggs and Kunkel as a project that could answer some of their questions about the uniqueness of the eye muscles. They agreed to take her on.
“We did what I felt would be most exciting and meaningful in the long haul. Just follow the trail wherever it leads us.”
Engle and Beggs drove to the toddler's home in New Hampshire and spent an afternoon sitting in the family's kitchen meeting relatives affected by the disorder. Engle collected blood samples, Beggs labeled the tubes, and they both observed the signs of CFEOM. They would do this many more times over the next three years. As she'd hoped to do, Engle learned the ins and outs of running a genetics study—everything from enrolling patients to using the novel technologies of the 1990s to zero in on the genetic mistake causing a disorder.
"The time that we worked together was marked by a very steep learning curve for Elizabeth," says Beggs. "And she learned things much faster than anyone I've ever worked with."
Only a few years later, in 1994, Engle's search for the gene causing CFEOM type 1 led her to the center of chromosome 12—one of the 23 chromosome pairs in which every human cell packages its genetic information. Frustratingly, at that time the centers of chromosomes were notoriously hard to decode, packed with the most complicated and repetitive strings of DNA. But the Human Genome Project was under way, and Engle knew it wouldn't be long until other scientists published a complete genetic map of chromosome 12. So she made a calculated move: she stepped back to wait for the map of the chromosome before finishing her gene hunt.
Her lab spent the next several years building up what Engle calls their "treasure chest" of rare eye disorders—finding families, defining their disorder, and then determining which ones fell into groups. "I admit I am a tenacious individual," says Engle. "I would travel all over the country finding families. I would wait in someone's driveway until midnight when they got home so I could enroll them in our study, because maybe they'd be the person that would get us that much closer to a gene."
By 2003, Engle had pinpointed the mutations that cause CFEOM type 1, as well as CFEOM type 2, which she'd discovered in families in the Middle East. Both mutated genes suggested that the root cause of CFEOM disorders was in the development of neurons, not in the stiffening of the eye muscles (as was previously thought and suggested by the "fibrosis" in CFEOM). Engle was intrigued by exactly how the genetic mutations caused the developmental problems. But she knew little about this area of biology.
Her lab had the choice of continuing to identify genetic causes of eye disorders, and then pass the genes along to other groups to study, or delving into the molecular details of the disorders themselves. She chose the harder path, heading straight to developmental biology textbooks. "We did what I felt would be most exciting and meaningful in the long haul," Engle says, "just follow the trail wherever it leads us."
That same year a graduate student in neurobiology approached Engle, interested in working in her lab. Max Tischfield arrived at just the right time and was a key player in the lab's evolution over the next seven years, bringing his own expertise in developmental neuroscience, and basic research, to the then largely clinically oriented lab. He led the effort to study the latest set of gene mutations that the Engle lab had discovered—work that drew the lab into studying the role of microtubules in nervous system development.
Tischfield, now a postdoctoral fellow in the lab of HHMI investigator Jeremy Nathans at Hopkins, says, "I'm very proud of where Elizabeth's lab is today. When I joined, the lab was very much clinicians, trying to classify these diseases. Now, there are experimental neuroscientists, cell biologists, geneticists. That was the natural transition that the lab was headed for, and I'm very glad I got to be there for that."