A new group of HHMI investigators tackles basic research questions by splitting time between the laboratory and the clinic.

Left to right, beginning with top row: Elizabeth C. Engle, M.D.; S. Ananth Karumanchu, M.D.; Charles L. Sawyers, M.D.; Vivian Cheung, M.D.; Arul M. Chinnaiyan, M.D., Ph.D.; George Daley, M.D., Ph.D.; David H. Rowitch, M.D., Ph.D.; Erol Fikrig, M.D.; Joseph G. Gleeson, M.D.

A 1992 encounter with a toddler whose eyes were frozen in a downward gaze led pediatric neurologist Elizabeth C. Engle to discover a trove of previously unrecognized congenital disorders. Over the last 16 years she has explored the clinical and genetic features of these syndromes, caused by errors in brain-stem motor-neuron development, which rob patients of normal control of their eye movements.

Engle's commitment to both patient care and research was just what HHMI had in mind when she and 14 other patient-oriented researchers were selected as HHMI investigators last fall. The new HHMI investigators represent 13 institutions from across the United States. In all, 40 finalists were chosen from among 242 applicants, and 15 were selected to become HHMI investigators. The Institute has committed approximately $150 million to their first term of appointment.

These physician-scientists "have demonstrated extraordinary creativity and innovation," says Institute President Thomas R. Cech, and they "are changing the way we think about—and treat—a variety of diseases."

When Engle first met her young patient at Children's Hospital Boston, she simply wanted to diagnose the child's problem. Ophthalmologists thought it was congenital fibrosis of the extraocular muscles, a rare birth defect generally believed to result from rigid scar tissue replacing the muscles that pull the eyeball down. Engle agreed that the patient fit the clinical description for this disorder; however, she was left wondering if his eye movement disorder might result from an error in neuron development rather than primary muscle fibrosis.

Learning that the boy's extended family had 20 similarly affected members, Engle worked with the Children's Hospital laboratories of Alan Beggs and HHMI investigator Louis Kunkel to conduct a systematic study that combined clinical and genetic analyses.

The family would notify her when an elderly relative died of other causes, and she would then examine the deceased's eyeballs and their surrounding muscles. Engle found that while the muscle that pulled the eye down was defective, it was not a mass of scar tissue; the muscle was simply contracted, keeping the eyeball pointed at the ground. Moreover, the muscles that pulled the eye upward were absent altogether, and so was the cranial nerve connecting them to the brain stem. Muscle fibrosis was not the correct diagnosis after all.

Looking for case reports and families with similar conditions, Engle pored over journals and contacted clinicians around the world, ultimately locating more than 700 families affected by this newly described disorder or others related to it. Then, using DNA linkage and mutation analysis, she identified the genetic causes for a series of these disorders, each of which perturbed development of one or more cranial nerves. The syndromes, now termed "congenital cranial dysinnervation disorders" (CCDDs), include Duane syndrome, horizontal gaze palsy, Moebius syndrome, and congenital ptosis.

Engle and her colleagues found that CCDDs were caused by two kinds of mutations—in genes that encode transcription factors crucial to cranial motor-neuron development, and in genes for proteins that help growing nerve axons connect to appropriate targets. The mutation passed down to some members of the original toddler's family, for example, scrambles the gene for a particular kinesin—a motor molecule that shuttles nutritional and structural cargo through nerve cells. When it is defective, the nerves are starved of critical resources and fail to develop normally.

Photos: Engle: Walter Urie for Children's Hospital, Boston, Karumanchu: Kaye Evans-Lutterodt / PR Newswire, ©HHMI, Sawyers: Liz Baylen / PR Newswire ©HHMI, Cheung: Peter Wodarcyzk / PR Newswire ©HHMI, Chinnaiyan: Don Alley / PR Newswire ©HHMI, Daley: Kaye Evans-Lutterodt / PR Newswire, ©HHMI, Rowitch: Andy Kuno / PR Newswire, ©HHMI, Fikrig: Robert Lisak / PR Newswire ©HHMI, Gleeson: Fred Greaves / PR Newswire ©HHMI

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