William B. Dobyns, MD is the 2018 Bernard Sachs Awardee. He is a prolific physician-scientist and mentor with influential contributions to the fields of child neurology, developmental neuroscience, and human genetics. Bill is the second son of an Air Force physician and Army nurse who met in the aftermath of WWII. His childhood years criss-crossed the continent, culminating in graduation from high school in Rochester, Minnesota where his father was an Orthopedic Surgeon at the Mayo Clinic. He graduated from the University of Michigan in 1974 and received his medical degree from Mayo Medical School in 1978. He completed pediatrics training (and met his future wife, Sara) at the Gundersen Clinic and Lutheran Hospital in LaCrosse, Wisconsin from 1978 to 1980. He went on to a pediatric neurology residency at Baylor College of Medicine from 1980 to 1983, a program then led by Marv Fishman who proved to be a wonderful mentor as well as a strong supporter of his early interest in research. He also began a productive collaboration with cytogeneticist Dr. David Ledbetter; their work led to the discovery of chromosome 17 deletions in Miller-Dieker syndrome. He completed a fellowship in medical genetics at the Mayo Graduate School of Medicine in 1985, becoming one of the first physicians to complete combined training in pediatric neurology and genetics.
Bill began his first faculty position as Assistant Professor at the Medical College of Wisconsin from 1985 to 1989. He then made a series of professional moves (probably more than he would have preferred) that exposed him to a wide range of mentors and research opportunities. He was promoted to Associate Professor in 1989 with his move to Indiana University School of Medicine where he stayed until 1992. He next moved to the Twin Cities with an appointment at the University of Minnesota Medical School from 1992 to 1998, where he was able to significantly expand his research program with strong and consistent support from Drs. Ken Swaiman, Phyllis Sherr, and Larry Lockman. With the mentorship of Larry Lockman, Bill was awarded his first successful NIH grant as Principal Investigator. In 1999, he was promoted to Professor at the University of Chicago where he opened his first research laboratory as primary investigator. It was here that he recruited and began a very productive and longstanding scientific collaboration with Dr. Kathy Millen. Finally, in 2010, he and Dr. Millen were recruited to join an expanding Neuroscience research unit at Seattle Children’s Research Institute and the University of Washington School of Medicine, where his contributions to our field continue.
Bill’s research interests are wide-ranging and include studies of a large and diverse group of developmental brain disorders that include brain malformations as well as pediatric epilepsy, movement disorders, autism and severe autism-plus disorders (developmental encephalopathies), medical and molecular genetics, and most recently genetic mosaicism underlying developmental brain and vascular disorders. With work over many years, he developed expertise in both brain imaging and molecular genetics, using these as essential tools to define the nature and underlying causes of many genetic and non-genetic developmental disorders. He has achieved extensive private and public grant funding including consistent NIH grant funding since 1989. He has given more than 150 invited lectures and published 370 manuscripts as well as 45 chapters and reviews. His lifetime key research collaborators have been Drs. Elizabeth Ross (who first taught him how to write a grant!), David Ledbetter, Jeff Golden, Joe Gleeson, Jim Barkovich, Elliott Sherr and especially Kathy Millen. With his colleagues and collaborators, Bill has contributed to:
- The initial recognition and or primary definition of numerous well known clinical syndromes (Miller-Dieker syndrome (MDS), Walker-Warburg syndrome, Smith- Magenis syndrome [SMS], Baraitser- Winter cerebrofrontofacial syndrome, Joubert syndrome, X-linked lissencephaly with abnormal genitalia, Warburg Micro syndrome, megalencephaly-capillary malformation syndrome, megalencephaly-polymicrogyria-polydactyly- hydrocephalus syndrome, coloboma-renal syndrome, rapid-onset dystonia-parkinsonism and more).
- The discovery of three important microdeletion syndromes (17p13.3 [MDS], 17p11.2 [SMS] and 16p11.2 [autism and other neurodevelopmental phenotypes]).
- The delineation of many more disease-causing copy number variants.
- The discovery of 22 causative gene mutations associated with diverse developmental neurological disorders.
- Co-discovery of another 30 genes (most associated with developmental brain disease).
- Many other studies defining various neurological disease and syndromes often with state-of-the-art genotype- phenotype correlations.
For nearly three and a half decades, Bill’s contributions have helped to establish the field of Developmental Neurogenetics. His interest in brain malformation began during his child neurology training under Dr. Marvin Fishman at Baylor College of Medicine in Houston when he saw his first three patients with lissencephaly, two found to have structural abnormalities of chromosome 17p13. In the subsequent years, he gathered data on patients across the country and began to differentiate syndromes with CT and then MRI. This work was the basis for future genetic studies that have led to the discovery of many genes associated with lissencephaly (LIS1, YWHAE, DCX, ARX, ACTB, ACTG1, CRADD and most recently MACF1). Bill coined the term ‘malformation of cortical development’ and contributed heavily to our understanding of this large group of malformations. More recently, his laboratory has used whole exome sequencing technology to discover five causative genes (PIK3CA, PIK3R2, AKT3, CCND2, MTOR) in the pathway underlying megalencephaly, hemimegalencepahly and focal cortical dysplasia type.
Dr. Kathy Millen has been Bill’s most vital career collaborator (first at the University of Chicago and now at Seattle Children’s and the University Washington in Seattle). Using a mouse model of hemimegalencephaly, this collaboration has recently reported a rapidly reversible epilepsy using a PI3K-specific inhibitor. This collaboration has also led to the discovery of the first three genes associated with Dandy-Walker malformation (ZIC1, ZIC4 and FOXC1). Bill has also played an important role in the delineation of malformation of the early forebrain such as holoprosencephaly, agenesis of the corpus callosum, septo-optic dysplasia as well as congenital and early life hydrocephalus. This work has included the delineation of phenotypes, gene discovery, and genotypic-phenotypic correlations.
In addition to his important scientific contributions, Bill has been an effective mentor to many successful neurology and genetic residents (32), graduate students (5), and post-doctoral fellows (17). His mentored grant funding includes four K or equivalent awards (Alex Paciorkowski [K08], Hannah Tully [KL2], Ghayda Mirzaa [K08], and Jimmy Bennett [Burroughs Wellcome Fund Career Award]). Some of his greatest satisfaction has come from his trainees continuing research in developmental brain disorders after leaving his lab.
With Bill’s depth of knowledge in brain development and malformation, he was perfectly positioned to understand and educate us about congenital Zika syndrome. In addition to several recent publications on this topic, his presentation of Zika syndrome was a timely highlight of the 2016 Child Neurology Society meeting in Vancouver BC.
Bill’s research interests are wide-ranging and include studies of a large and diverse group of developmental brain disorders that include brain malformations as well as pediatric epilepsy, movement disorders, autism and severe autism-plus disorders (developmental encephalopathies), medical and molecular genetics, and most recently genetic mosaicism underlying developmental brain and vascular disorders.