Children’s Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania │ Philadelphia, Pennsylvania
For demonstrating the maternal inheritance of mitochondrial DNA (mtDNA) in humans, using mtDNA variation to reconstruct ancient human migrations, identifying the first mtDNA mutation associated with an inherited disease, and showing that mutant mtDNA can profoundly affect the nuclear genome, causing complex diseases, thereby leading the way to therapies for those diseases and the aging process.
In the early 1970s, when Douglas Wallace was earning his Ph.D. in microbiology and human genetics at Yale University, researchers confined their study of genes to those in the nucleus of a cell. Nuclear DNA remains the focus of most DNA studies today. But Wallace, who studied genetics and developmental biology as an undergraduate at Cornell and spent two years of military service at the U.S. Public Health Service as a research microbiologist, was interested in learning more about a different type of DNA—mitochondrial DNA.
Mitochondria are tiny organelles, located in the cytoplasm of every cell, that generate energy for the cell from food. They contain their own circular mitochondrial DNA (mtDNA) molecules; in humans, the 16,569 base pairs encode 37 mitochondrial genes. Taking a cue from physics, Wallace approached biology with the understanding that energy is “the most important thing.” “And the thing that made the most energy was mitochondrial; it couldn't be trivial. And if it had its own DNA, it must mutate and that must cause a change in its characteristics and that might cause disease. So I thought it was obvious that one would study mitochondrial energy, and their role in disease,” Wallace said about his choice to focus on the mitochondrial genome.
After completing a postdoctoral fellowship at the National Institutes of Health, Wallace spent seven years as an assistant professor at Stanford University, where he made the discovery that unlike nuclear DNA, mitochondrial DNA is inherited from the mother only. Based on this insight, Wallace was able to track ancient human migrations by analyzing shared patterns of mtDNA sequences in modern populations. For example, he was able to identify humans’ expansion from Africa to Asia 150,000 years ago, followed by migration into Eurasia and eventually the Americas.
In 1983 he took a position as a professor of biochemistry at Emory University, where he continued his research on maternal inheritance and disease. During nearly two decades at Emory, he launched the Center for Molecular Medicine and the Department of Genetics and Molecular Medicine. He discovered a range of diseases inherited through mutations in mtDNA, including one known as Leber’s hereditary optic neuropathy (LHON), which causes sudden-onset blindness in adults.
Wallace’s pioneering work with inherited mitochondrial diseases led him to investigate the potential mitochondrial cause of a variety of degenerative diseases. He accurately hypothesized that mutations causing damage to mitochondria, the cell’s energy center, can contribute to ailments like heart disease, type 2 diabetes, chronic muscle weakness, movement disorders, and dementia. Wallace began studying aging tissue in an effort to further understand mtDNA’s role in those age-related diseases. His findings revolutionized how scientists view mutations in mtDNA genes and launched the field of mitochondrial medicine. Wallace determined that mtDNA acts as an “aging clock,” with mutations accumulating in different tissues as we age. He followed up human tissue experiments with studies on mice and proved that a build-up of mtDNA mutations leads to the onset of the same degenerative diseases in rodents as found in humans.
Following his time at Emory, Wallace spent nearly a decade at the University of California, Irvine where he founded the Center for Molecular and Mitochondrial Medicine and Genetics. In 2010 he moved to the Children’s Hospital of Philadelphia and founded the Center for Mitochondrial and Epigenomic Medicine. Wallace is the center’s director and a professor of pathology and laboratory medicine at the University of Pennsylvania.
Wallace’s honors include the American College of Physicians Award for Outstanding Work in Science as Related to Medicine, the Gruber Foundation Genetics Prize, the William Allan Award of the American Society of Human Genetics, and many citations for excellence in teaching.
Douglas Wallace’s curiosity about mitochondria has yielded tremendous insights into human biology, from our past history to our future health. With his spark of inspiration that a tiny circle of DNA could have far-reaching impacts, Wallace continues to be a trailblazer in his field.
Information as of April 1, 2017