Dr. Elizabeth Engle is a quintessential child neurologist physician-scientist who single-handedly established a new field of investigation into disorders of cranial nerve development. The impact of her work has been enormous in defining new congenital syndromes and their genetic etiologies and in delineating mechanisms underlying motor neuron and axon development in health and disease.
Dr. Engle grew up in Columbus, Ohio, as the daughter of two Ohio State University professors. She excelled at studying cello and traveled the world before becoming the remarkable physician-scientist we know today. After graduating summa cum laude from Middlebury College, Dr. Engle received her medical training at Johns Hopkins University School of Medicine. She trained for three years in pediatrics at Johns Hopkins, one year in neuropathology at Massachusetts General Hospital, and three years as an adult and child neurology resident in the Longwood / Boston Children’s Hospital (BCH) program. After postdoctoral research training in Genetics with Alan Beggs and Lou Kunkel, she joined the faculty in 1997. Dr. Engle quickly rose through the ranks to become full Professor at Harvard Medical School in 2008, the same year she was appointed as an Investigator of the Howard Hughes Medical Institute.
Dr. Engle became interested in the genetic and neurodevelopmental basis of cranial motor neuron disorders following a clinical encounter in 1992 during her senior residency year at BCH. She saw a one-year-old and many of his relatives with congenital ptosis and with both eyes ‘fixed’ in a downward position. He was diagnosed with the rare autosomal dominant disorder ‘congenital fibrosis of the extraocular muscles’ (CFEOM), a disorder of unknown cause thought to be due to primary fibrosis of the extraocular muscles. Dr. Engle hypothesized that CFEOM resulted not from primary muscle fibrosis but, instead, from a primary defect in cranial nerve development, and in the era of the early days of the Human Genome Project, she used a genetic approach to test her hypothesis. She began collaborating with clinicians worldwide to identify additional families with complex eye and facial movement disorders to define their phenotypes and genetic etiologies.
Dr. Engle established her laboratory at BCH in 1997, where she expanded her studies to encompass the genetics of other complex strabismus syndromes, including various forms of CFEOM, Duane retraction syndrome (DRS), horizontal gaze palsy (HGP), congenital ptosis, Moebius syndrome, and synkinesis syndromes. Her lab has pioneered the discovery of many genes that, when mutated, cause complex strabismus, and the lab contributed to reports of many more, often for previously unrecognized syndromes that her team defined through careful phenotyping. Supporting her initial hypothesis, detailed mechanistic studies in animal models revealed that these disorders do indeed result from errors in the development of neurons and their axonal connectivity. These include genes essential to midline crossing of axons destined to synapse on ocular motor neurons (ROBO3) or to ocular motor neuron development (HOXA1, PHOX2A, MAFB, SALL4) and genes that, when mutated, alter ocular motor axon growth and guidance (KIF21A, TUBB3, TUBB2B, TUBA1A, CHN1, ACKR3). She has extended her work to encompass inherited forms of congenital facial weakness caused by coding variants in HOXB1 and non-coding variants altering GATA2 expression, both of which alter facial motor neuron identity. Collectively, her work defined a new category of birth defects now named the ‘congenital cranial dysinnervation disorders’ (CCDD) that result from aberrant signaling to the extraocular and cranial muscles by motor neurons in the central nervous system.
Through her clinical and scientific insights, Dr. Engle recognized that cranial motor neurons provide a powerful study of normal and aberrant neurodevelopment. Small numbers of cranial motor neurons cluster together to form distinct brainstem nuclei. Each motor neuron must acquire the correct identity, migrate to its final destination, and send its axon along a stereotypic trajectory to innervate its target muscle. CCDDs perturb these genetic programs during early development, resulting in congenital, lifelong phenotypes that are visible to the examiner such that one can predict the cranial nerve that has failed to develop correctly. Her lab has focused much of their mechanistic work on genes that, when mutated, cause errors of axon growth and guidance through alterations in the microtubule and actin cytoskeleton (e.g., CFEOM1 and CFEOM3).
Most recently, Dr. Engle has taken on a major challenge in human genetics – how to interpret and prove causality of non-coding variants. Studying thirteen families with hereditary congenital facial paresis type 1 (HCFP1), her lab identified a series of single nucleotide variants within a 30 bp segment of a highly conserved regulatory non-coding DNA element (cRE) and a series of duplications of this and two adjacent cREs. Coupling neurodevelopmental studies with single cell RNA- and ATAC-sequencing of wildtype and humanized mutant mice, the lab determined that these variants altered GATA2 expression in a cell-type specific fashion. They rescued the mouse facial weakness phenotype by downregulating a downstream target gene (GATA3), identified the transcription factor that binds to the conserved element specifically in developing facial motor neurons, and demonstrated a delay of a normal shift in cell identity resulting in a paucity of facial motor neurons. This tour-de-force series of experiments provides a blueprint for characterizing non-coding variants in human genetics.
In addition to her innovative and highly successful scientific contributions, Dr. Engle is highly committed to training the next generation of neuroscientists and child neurologists. She is a gifted mentor and source of support to students, fellows, and faculty throughout BCH. She is co-PI of an NINDS T32 training program for postdoctoral fellows and is passionate about issues around diversity in biomedical sciences, serving as co-chair of the BCH Equity, Diversity, and Inclusion Research Committee. Dr. Engle has published many high-impact papers, given invited lectures, and served as a visiting professor at many universities and research institutions. She has received multiple prestigious awards, including the E. Mead Johnson Award from the Society for Pediatric Research and the Sidney Carter Award from the American Academy of Neurology. She was elected to the Association of American Physicians in 2012, the National Academy of Medicine in 2019, and the American Academy of Arts and Sciences in 2023. She remains an HHMI Investigator. Her outstanding body of work has been enabled, in great part, by the wonderful support of her husband, Paul Dennehy, and their daughter, Saoirse, who is a rising senior at the University of Michigan.
In summary, Dr. Elizabeth Engle is an outstanding child neurologist and physician-scientist whose insights and discoveries defined a new field of investigation into disorders of cranial nerve and brainstem development. Her scientific success has impact on a wide range of disorders, from rare congenital disorders of cranial nerve development to one of the most common childhood disorders, strabismus. She is a passionate mentor, sponsor, and advocate of trainees and junior faculty from diverse backgrounds. Dr. Engle has received national and international recognition at multiple platforms, serving as a role model for physician-scientists in child neurology.