2012 Gruber Genetics Prize

Four decades ago, when other scientists were looking for genes in the nucleus of cells, Douglas C. Wallace decided to research genes elsewhere: in the cells’ mitochondria. Found in the cytoplasm of all human cells, mitochondria are structures that serve as the cell’s primary “power generator,” converting energy from food into a form that the cell can use. They 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.

Wallace began by defining the genetics of the mtDNA. He then made the seminal discovery that mtDNA in humans is inherited exclusively through the mother, a finding that he published in 1980 in a landmark paper. Using maternal inheritance as a guide, Wallace went on to identify, for the first time, inherited mtDNA diseases. The first two of these identified diseases were Leber’s hereditary optic neuropathy (LHON), a rare disorder that causes a sudden and disabling loss of central vision, and myoclonic epilepsy and ragged red-fiber (MERRF) disease, another rare disorder that produces a variety of symptoms, including epileptic seizures, muscle spasms, deafness and dementia. Wallace also found that the degree of mutant mitochondria within an affected family established the severity of these diseases’ symptoms.

Wallace subsequently demonstrated that mutations in mitochondrial genes play a role in the complex degenerative diseases that develop in aging adults, such as diabetes, heart disease, kidney disease, and Alzheimer disease. For example, one mtDNA mutation arose in humans between 8,500 and 17,000 years ago but today is found in 3 percent of people with late-onset Alzheimer disease, in 5 percent of people with late-onset Parkinson disease and in 7 percent of people with both diseases, yet is only found in 0.4 percent of the general population.

Wallace also discovered that mtDNA mutations accumulate in aging tissues and that those tissues with the highest levels of mtDNA mutations are also those most commonly affected in age-related degenerative diseases. This led to his proposal that the accumulation of mtDNA mutations was the aging clock and that this explained the delayed-onset and progressive course of many common diseases. To confirm that mtDNA mutations were sufficient to cause complex diseases, Wallace and associates developed procedures for introducing mtDNA mutations into the mouse and showed that mtDNA mutant mice developed the symptoms of complex degenerative diseases. These groundbreaking discoveries have changed the way medical geneticists think about the role of mitochondria in health and disease and have helped to launch the field of mitochondrial medicine.

Wallace’s research has also made a major contribution to the field of molecular anthropology. Using mtDNA variation, he has reconstructed the origins and ancient migrations of women, tracing all mtDNA lineages back some 200,000 years to a single African origin—the so-called mitochondrial Eve. His work in this field has led him to propose that mtDNA mutations are adaptive, helping migrating populations modulate their cellular metabolism to survive and thrive in new environments.