Douglas C. Wallace | Gruber Foundation

Even during his childhood, which was spent near Annapolis, Maryland, and in the Long Island town of Sayville, New York, Douglas C. Wallace had a strong interest in genetics and biology. “I was always asking the questions, who am I, where did I come from, and why do I generally feel bad,” he remembers with a laugh. That interest in what he calls “the fundamental aspects of being alive” took him first to Cornell University in Ithaca, New York, where he studied genetics and developmental biology, and then (after two years in the U.S. Public Health Service as a research microbiologist) to graduate school at Yale, where he received his PhD in 1975 in microbiology and human genetics.It was while at Yale that Wallace developed his passion for what would become his life work: mitochondrial DNA (mtDNA). At the time, most geneticists were searching for genes in the nucleus of cells. Wallace, however, was intrigued by a much smaller set of genes found in cellular structures known as the mitochondria. Located in the cytoplasm of all human cells, mitochondria are often described as the cell’s primary “power plants” because they convert energy from food into a form that the cell can use. But mitochondria also contain a tiny strand of DNA—essentially, a second human genome. Wallace recognized what few others did at the time: that studying the mitochondrial genome would be as crucial to understanding the human body and human disease as similar efforts involving the much larger nuclear genome. “I wanted to work with mitochondria,” Wallace says. “My rationale was that anything that provided 90 percent of a cell’s energy couldn’t be trivial, and anything that had DNA must mutate and lead to disease.”Wallace took an assistant professorship at Stanford University in 1976 and then, in 1983, went to Emory University where he stayed for the next 19 years, initially as professor of Biochemistry and ultimately establishing the Center for Molecular Medicine and the Department of Genetics and Molecular Medicine. While at Stanford, he had published his landmark paper on the discovery that mtDNA in humans is inherited exclusively through the mother. At Emory, he used that maternal inheritance as a guide to identify, for the first time, an inherited mtDNA disease: Leber’s hereditary optic neuropathy (LHON), a rare disorder that causes mid-life sudden-onset blindness. He subsequently linked mtDNA mutations to other rare diseases with a multitude of clinical symptoms, including deafness, neuropsychiatric disorders, and heart and muscle weakness.Wallace suspected, however, that defective mitochondria played a role not just in inherited diseases, but also in many of the chronic and common degenerative diseases associated with aging, such as heart disease, type 2 diabetes, muscle weakness, movement disorders and dementia. Because these diseases frequently had a delayed onset and progressive course, Wallace started studying mtDNA mutations in aging tissue. He found that not only do mtDNA mutations accumulate in aging tissue, but those tissues with the highest levels of mtDNA mutation are also the ones most commonly affected in age-related degenerative diseases. “These somatic mutations proved to be the aging clock,” Wallace explains. “They offer a whole new way of looking at common complex diseases.” Concurrently, Wallace and is colleagues developed mice harboring mtDNA mutations and showed that this caused the same symptoms as seen in people thus proving that the mtDNA mutations could cause these complex diseases.Wallace’s discoveries revolutionized the way geneticists and other scientists think about the role of mitochondria in health and disease. They also helped launch the field of mitochondrial medicine. But his research has made a major contribution to another area of scientific inquiry as well: molecular anthropology. Using mtDNA variations, Wallace reconstructed the origins and ancient migrations of women, which in parallel with work from Allan Wilson’s laboratory led to the so-called “mitochondrial Eve” concept that all human mtDNAs trace back to a single African origin some 200,000 years ago. His work in this field has led him to propose that mtDNA mutations are adaptive, helping migrating populations modulate their cellular metabolism. “The mtDNA variations have changed human physiology,” Wallace explains, “which has allowed people to live in different climate zones.”In 2001, Wallace left Emory for the University of California in Irvine, where he founded the Center for Molecular and Mitochondrial Medicine and Genetics. Then in 2010, Wallace moved his center to Philadelphia where he became the founding director of the Center for Mitochondrial and Epigenomic Medicine at the Children’s Hospital of Philadelphia and a professor of Pathology and Laboratory Medicine at the University of Pennsylvania. “The hospital wanted a mitochondrial medicine program, and that is what I really wanted to do,” he says.Wallace has received numerous honors and awards during his distinguished career, including memberships in the National Academy of Sciences in 1995, the American Academy of Arts and Sciences in 2004, and the Institute of Medicine in 2009. He currently lives in the Philadelphia area with his wife of 44 years, Elizabeth (Betty), who is an artist and photographer. They have two children, Lisa and David.