As a student, Ralph DeBerardinis found cellular metabolism boring. The black-and-white diagrams of biochemical pathways in his textbooks did little to ignite his imagination. Then he saw how disruptions in those pathways wreaked havoc on his patients, and suddenly, the complex networks had his undivided attention.
DeBerardinis began treating children with inherited metabolic disorders during his medical residency at the University of Pennsylvania and Children’s Hospital of Philadelphia. His patients’ symptoms, brought on by the absence of an essential metabolite or the accumulation of some toxic compound, were often sudden and severe. Most of the children lacked a single metabolic enzyme – one of hundreds the body uses to convert nutrients to energy and generate cellular components.
“Missing any one of those enzymes means that you can get very sick, very quickly. And the symptoms depend on which enzyme is missing, meaning that different pathways support health in specific ways,” DeBerardinis says. Many such problems can be corrected with dietary modifications, but there are hundreds of ways metabolism can go wrong.
Most children with an apparent metabolic disorder never receive a definitive diagnosis – “probably because we haven’t discovered the underlying gene yet,” DeBerardinis says. But when he first set out to explore these problems in the lab, he found potential mentors skeptical. “I think the perception then was that we already knew all the metabolic pathways,” he says.