Outsider looking in

Exploring the tiniest of places, geneticist Douglas Wallace is onto something really big

“Who are we? Where did we come from? Why do we suffer so?” For four decades, Douglas Wallace, Donald Bren Professor of Biological Sciences and Molecular Medicine and director of UCI’s Center for Molecular and Mitochondrial Medicine and Genetics, has worked to find answers to these giant questions in a tiny place: the energy-regulating parts of the cell known as the mitochondria.

Mitochondrial analysis has allowed Wallace to explore the relationship between human evolution and some of the world’s most common and disabling diseases, including diabetes, Alzheimer’s, seizure disorders and Parkinson’s. The degenerating effects of aging itself may largely be fueled by accumulated mutations in the mitochondria, and the resulting malfunction of organs and systems throughout the body, says Wallace. Many of these malfunctions have their roots in evolutionary adaptations hidden in the history of the human species.

“If you want to know why we are the way we are, including why we get the diseases we do, you have to understand our evolutionary history,” Wallace says.

In February 2006, he received a $2.25 million award from the Doris Duke Charitable Foundation to study how metabolic disorders may be triggered by genetic changes in the mitochondria. Using DNA samples from patients of Chinese heritage living in Taiwan and in Southern California, the study may lead to a greater understanding of the metabolic syndrome – the risk factors behind diabetes, obesity, hypertension, high cholesterol and cardiovascular disease – and provide new approaches to their diagnosis and treatment.

Wallace’s radical reinterpretation of the nature of so many common diseases has placed him on the outside of mainstream science, but, he says, “I’ve grown comfortable being on the outside. I’m used to it.”

It is a testament to both his courage and his eccentricity that he chose to study mitochondria at all. When he was a graduate student at Yale in the late 1960s, it was assumed that what happened in the mitochondria, which are found outside the nucleus of the cell, was much less interesting and important than what happened inside. Mitochondria have their own DNA, distinct from the more celebrated and much longer DNA molecules found in a cell’s nucleus. But in those days, geneticists thought mitochondrial DNA (mtDNA) had no significant influence on recent human evolution or common diseases. Wallace disagreed.

“If it was DNA, I assumed it could mutate,” he recalls. “And if it could mutate, it could cause disease.” Furthermore, he says, “Anything that provided 90 percent of the human body’s energy [as the mitochondria do]couldn’t be trivial.” His dissertation showed that mtDNA did indeed mutate, a discovery that launched the field of mitochondrial genetics.

Wallace’s ongoing research into the key role mitochondria play in health and history has led to his induction into the National Academy of Sciences and earned him the respect of his colleagues.

“Wallace’s science bridging anthropology and medicine is fantastic,” says Francisco Ayala, the renowned geneticist and University Professor and Donald Bren Professor of Biological Sciences. “It fits together so neatly. He is the top person doing this kind of work.”