Elizabeth Engle doesn’t often treat patients these days. But her innate clinical instincts were on full display from the moment we met last winter. In emails setting up our interview, I had casually mentioned that I have a close relative with one of the congenital eye movement disorders that have been her specialty – disorders so rare that it struck me as a noteworthy coincidence. When I arrived at her office at Boston Children’s Hospital a few weeks later, she launched right into pediatric neurologist mode: At what age was my relative’s eye problem first noticed? How did it manifest itself? Did this person also have weird thumbs?

This clinical drive has propelled Engle in her work on these syndromes, known collectively as congenital cranial dysinnervation disorders (CCDDs). Indeed, it was her encounter with one particular patient more than 25 years ago that led her to stumble, almost by accident, onto what would become her life’s work.

“I think of my research career as having three chapters,” she told me in her sunny office in the Boston Children’s Hospital Center for Life Science, its city view filtered through shelves of orchids, heather, and other greenery. Each chapter opened a new line of inquiry without closing the previous one, meaning that right now Engle, who was selected as an HHMI investigator in 2008, is juggling all three chapters at once. Chapter One is about identifying genes, Chapter Two is about understanding mechanisms, and Chapter Three is about clarifying the steps of normal neurodevelopment. They all revolve around CCDDs, which have proved a surprisingly rich way to answer some complex questions about how brain growth occurs and how it can go wrong.

Chapter One in Engle’s scientific biography began in 1992, when she was living in Boston after having completed an unusually long stretch of medical training: 11 years total, starting with medical school and a pediatric residency at Johns Hopkins University in Baltimore, followed by a move to Boston for a fellowship in neuropathology at Massachusetts General Hospital, and then a second residency in neurology at Boston Children’s. The goal was a career as an academic physician-researcher, which Engle considered the ultimate intellectual challenge. The next step, then, was to learn how to do research in the field that had caught her fancy early on: human genetics. She needed to find a laboratory to hire her as a postdoc.

Looking for a way to begin her exploration, she remembered a little boy from New Hampshire she had met during her neurology residency. He had an eye movement disorder, called congenital fibrosis of the extraocular muscles (CFEOM), that also affected other members of his family. The boy and his relatives were unable to roll their eyes upward; if they wanted to look up, they had to move their heads. It seemed a perfect condition for genetic analysis: it was a dominant trait, evident at birth, easy to spot, and it caused such mild impairment that it didn’t interfere with a person’s ability to survive and reproduce, thus providing the large family cohorts necessary in the search for disease genes.

Engle thought a good place to go to look for the CFEOM gene would be the lab of Louis Kunkel, then an HHMI investigator and a legend in human genetics. Like Engle, he has spent his whole career studying a single disorder, in his case Duchenne muscular dystrophy, a degenerative muscle disease that affects virtually every muscle in the body except the extraocular muscles. Engle believed CFEOM might be the exact inverse, because it only targeted the extraocular muscles. Because of this “selective resistance,” she thought it might be enlightening to study the two disorders side by side. Along the way she hoped to get a crash course in human genetics from some of the best scientists in the field.

Engle’s work took 10 years to yield her first definitive finding: the genes that cause CFEOM type 1, which affected her first patient and his family, as well as those that cause CFEOM type 2, a variation she found in families from the Middle East. It turned out that patients’ inability to roll their eyes upward was not due to a stiffening of the orbital muscle, as had previously been thought, but to a problem with the connection that the cranial nerve establishes with that muscle. The connection occurs via the nerve cell axon, the roadway along which nerve impulses are carried. 

What’s especially handy about studying CCDDs – including Duane syndrome, horizontal gaze palsy, Moebius syndrome, congenital ptosis, and three types of CFEOM, among others – is that their effects are so obvious. If there’s faulty wiring in the connection of a nerve cell to a large muscle, the result might be difficult to spot – perhaps a slight limp if there’s trouble in the way the axon connects to a leg muscle, or a crooked smile if the trouble involves a muscle around the mouth. But the three cranial nerves that innervate the eye muscles are much more precise in their action, and it’s obvious when the two eyes fail to function. In effect, Engle had identified a simple model for a complex process. “If we can understand the wiring of these simple circuits,” she told me, “we may be better able to understand the wiring of more complex neural circuits as well.”

Tall and blond, with funky blue glasses and looking much younger than her age, Engle is quick to tell tales on herself and her own foibles. She told me about a friend who asked, about a year into their friendship, what exactly it was that Engle worked on in her lab.

“I study these rare eye movement disorders,” Engle began.

“What do you mean?” asked her friend.

“Well, like this rare disorder called Duane syndrome . . . .”

Her friend interrupted her. “You do know that I have Duane, right?”

Engle also investigates disorders such as Tubb3 syndrome, a disease that impedes eye movement control in children. Credit: VSA Partners (2011)/HHMI Bulletin

She didn’t know. She had never noticed that her friend had a quirk commonly seen in Duane syndrome, which limits a person’s ability to rotate one eye outward: she tended to position herself in a group so that people were sitting on her good side. Engle tells the story now as a joke about her own cluelessness, but at the time she was deeply embarrassed that despite her clinical experience and her much-vaunted scientific expertise, despite her Harvard appointment and her decades-long immersion in eye movement disorders, despite having interacted face-to-face with this woman for more than a year, she had totally missed the fact that her friend had Duane.

Chapter Two in Engle’s career opened up questions about the neurodevelopmental mechanisms behind these genetic eye disorders. This meant shifting some of her research attention from humans to animals. In 2005, she hired a mouse technologist, Michelle Delisle, who helped care for a growing colony of mice – now occupying about 600 cages a few floors down from the main lab – that were bred to have the genetic defects found in the various human CCDDs.

Using mouse models as well as zebrafish, Engle and her colleagues conducted functional studies of mutated genes and their normal and abnormal proteins. “We identify the mutation in humans,” she said, “and if we put it into the mouse we can recapitulate the human phenotype and then study why it happened.” What Engle has learned is that the trouble with eye movement is often caused not by a loss of gene function, but by altered or, on occasion, increased function. In Duane syndrome, for instance, they found that the overactivity of one protein, α2-chimaerin, impairs the ability of one small set of embryonic neurons to respond to growth signals. As a result, axon growth “stalls out” and never makes it to the target muscle.

Chapter Two in the lab overlapped with a new chapter in Engle’s personal life as well – her marriage in 2001 to Paul Dennehy, a photographer from Cork City, Ireland, whom she met through a mutual friend while on vacation in Nantucket. Two years later came the arrival of their daughter, Saoirse, whose name is Gaelic for “freedom.” They adopted her from China when she was 10 months old.

From the moment she brought Saoirse back to Boston, Engle wanted to be home with her as much as she could – which meant something had to give. But what? “I know it sounds odd, but I never had precise long-term career goals,” she told me. Rather than calculating each professional move in terms of how likely it was to elevate her status, she tended to choose new paths with her heart instead of her head. “I did medicine because I really loved it, trained in things I really loved,” she said. “This always led me to the next thing I loved. The only problem was when I loved too many things – which is what happened when my daughter entered my life. That’s when I had to figure out what was at the bottom of the love list.”

At the bottom, it turned out, was patient care. Engle did love treating patients, just as she loved so many aspects of her work, but it was love tinged with anxiety – Did she know enough? Was she doing enough? – and it took her away from her real passion – the science itself. She now restricts patient interactions to one afternoon a month, when she consults at the CCDD clinic she co-directs with a Harvard colleague, David Hunter. On clinic days, Engle spends a few hours with families of a child who has one of the eye movement disorders she studies in the lab. “It’s only a consultation, not ongoing care, so it’s not as stressful,” she said. “And it’s a chance to meet patients and help them, which is really fun for me.”

Now Engle has started Chapter Three in her scientific biography, in which she is trying to go beyond understanding the what of CCDD genes and their effect, to an understanding of the how. With this new chapter, Engle and her lab mates have started to focus on the process known as axon guidance, a critical piece of neurological development.

“There are not that many disorders that perturb the process, maybe because there are only certain circumstances where misguided axons can survive,” she said. “This leads back to the question of what’s normal development – which means, I think, that this next chapter will let us use these disorders to teach us about normal development as well.”

By focusing on the axon, Engle has also broadened the potential impact of her work. “Axon guidance disorders [may] soon be recognized as a new and significant category of human neurodevelopmental disorders,” she wrote in 2010 in the journal Cold Spring Harbor Perspectives in Biology. This includes such conditions as schizophrenia, autism, dyslexia, synesthesia, and depression. In addition, she wrote, understanding the particulars of axon guidance and connectivity might have an even bigger payoff: new insights into “the normal spectrum of human cognition and behavior.”

Engle had no special affinity for science as a child; she was a music nerd in high school, a loner who played cello in a community youth orchestra near her hometown of Columbus, Ohio. Her daughter isn’t especially science oriented, either; Engle describes Saoirse as a normal, well-adjusted 14-year-old, with dozens of interests and dozens of friends.

But as the child of two academics – her father taught English at the Ohio State University; her mother, a violist-turned-mathematician, was a math professor there – Engle felt that her intellectual options were limitless. Now she gives back by trying to enrich the options of students ordinarily shut out of careers like hers. She is active in the HHMI program EXROP, the Exceptional Research Opportunities Program, through which she recruits talented students from disadvantaged backgrounds to work in her lab every summer. She talks about the young people she’s helped train through EXROP with an almost maternal pride – and mentions the few with whom she’s lost touch with an almost maternal concern.

Still, sometimes she wonders if what she’s doing in her lab really matters. She was stung when her friend – the same friend who had the Duane syndrome that Engle failed to notice – bluntly asked her why she was “wasting” her time studying rare disorders that don’t kill anyone. “Why aren’t you studying something important, like cancer?” the friend asked.

Engle was hurt by the question, precisely because it’s one she occasionally asks herself. She has a tendency to dwell on matters of philosophy, such as how to define what the best use of a life would be. 

“Should I be asking more important, or at least more therapeutically relevant, questions?” she wondered aloud as the sun set outside her office window. “Maybe. But I’d rather understand mechanisms – how the body developed, how it got to be the way it is. How can you think about aging and degeneration if you don’t know how it all happened in the first place?” The questions Engle focuses on might seem narrow to some, but in her view they are basic and essential. And they’re particularly exciting questions to work on, because no one knows ahead of time what insights they might yield. ■

Story by Robin Marantz Henig
Photography by Jason Grow