PAGE 4 OF 4
Correcting Genetic Mistakes
Neurons are born amidst a concoction of chemical signals in a developing embryo's brain. Each cell's location in the brain is genetically programmed. Moreover, each neuron must stretch its long axon out to a specific location in the body—be it a big toe, a liver, or an eye muscle. To get there, each neuron follows chemical road signs, which interact with unique sets of surface proteins on each axon's tip. For the axon to lengthen, stiff structural filaments—called microtubules—arrange themselves in the right direction inside the neuron. Microtubules also become the highways that carry materials and messages between the axon and the neuron's control center, back in the brain.
Engle's lab has discovered that when it comes to the neurons that lead to the eye muscles, mistakes at any step of this process can lead to disorders. Some disorders are caused by a mutation in genes that give these neurons their identities. Others develop from mistakes in the proteins on the tips of axons. In these cases, the axons veer off in the wrong direction and never reach the eye. Microtubules that don't form properly cause another set of disorders, and malfunctioning molecular motors that carry cargo along the microtubules cause yet another, thwarting the relay of messages from the brain. Engle's team has linked mutations to seven complex eye movement disorders, including CFEOM types 1, 2, and 3; horizontal gaze palsy; and Duane's retraction syndrome.
"Wiring the brain to the periphery requires remarkable and complex genetic programs," Engle says, "and as you might imagine, these developmental programs can go wrong." Humans likely have variability in the exact projections of their axons to muscles, she hypothesizes, but in most cases, these errors probably go undetected. "A crooked smile is viewed as charming rather than debilitating. A small error in wiring to the huge quadriceps muscle may make you less of an athlete, but wouldn't be very noticeable."
But eye movements must be precisely controlled. Your left and right eye must point in the same direction, focus on the same object, and move at the same time for ideal vision. We use our eyes to communicate, express feelings, and explore our world. Complex eye movement disorders turn out to be sensitive indicators of wiring gone wrong.
Back to the Patients
Since 2008, Engle's been running a monthly clinic with David Hunter, chief of ophthalmology at Children's Hospital and vice chair of ophthalmology at Harvard. Hunter is a specialist in surgeries that, in some cases, can correct complex eye movement disorders. Patients come from around the world, and the two doctors pair up to consult with them—taking on only a couple of patients in an afternoon so they have ample time to explore every aspect of each case. Using the genetic information that Engle has uncovered gives Hunter a better idea of what symptoms to ask the patients about and what to expect when he goes into surgery.
Cases of the disorders vary greatly in severity. Some disorders affect both eyes and are often accompanied by other developmental disabilities; others rarely affect anything more than one eye. Some cause drastic paralysis of particular eye muscles, while others can be corrected with glasses or patches.
"We're at the stage now where we see these patients knowing what the mutation is, and so when I do surgery I at least know that going in," says Hunter. He can often tweak the placement of an eye muscle so that the eye's default position is forward, rather than a fixed gaze downward or to the side.
"A lot of people didn't think it was a good idea for her to study such rare disorders," Hunter says about Engle. "It's just a testament to her persistence that it didn't matter to her what people said. It wasn't about trying to make a big discovery, it was about trying to help these patients."
But bringing the science back to the patients is especially tricky in the case of CFEOM, Engle is the first to admit. "Translating genetic research back to the patient is often challenging," she says, "but for these complex eye movement disorders it is particularly so. These neurons are born and extend their axons at around 4 to 6 weeks of human gestation; the developmental errors occur before a woman may know she's pregnant."
Engle and Hunter's clinic offers diagnostics and genetic counseling for those more severely affected who want to prevent the disorder in their children. But scientists aren't yet at the point where they can interfere with early developmental processes in the brain once the disorder is inherited.
There are still plenty of questions about CFEOM and other complex eye movement disorders that Engle hopes to answer. Many of the genes that are mutated in these disorders are in every neuron in the brain, and in some cases, other organs as well. So why aren't other parts of the brain and body affected? And though Engle has identified the gist of how some of the mutated genes cause a disorder, there are still molecular caveats to work out. With a powerful new microscope that can zoom down to single molecules, for example, she's hoping to understand the effect that microtubule mutations have in the neurons leading to the eye. Is the microtubule too stiff or not stiff enough? Does cargo fall off the microtubules as it tries to move along? Does it stall in place? Where these questions will lead her next is anyone's guess.
Engle is incredibly devoted to her work and very intense—in a good way—says Beggs, and if anyone can answer these questions, she can.
"If reviewers of one of her papers come back and request some additional work that will take six months, a lot of authors might just try submitting it to another journal," says Beggs. "But she'll start whole new collaborations and learn new methods to address one of these questions. She's so precise in doing the best science that she can."