The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

But why did the same disease move with different velocities in different children? Knudson used the numbers and simple equations borrowed from physics and probability theory to model the development of the cancer in the two cohorts. He found that the data fit a simple model. In children with the inherited form of retinoblastoma, only one genetic change was required to develop the cancer. Children with the sporadic form required two genetic changes. This raised another puzzling question: why was only one genetic change needed to unleash cancer in the familial case, while two changes were needed in the sporadic form? Knudson perceived a simple, beautiful explanation. “The number two,” he recalled, “is the geneticist’s favorite number.” Every normal human cell has two copies of each chromosome and thus two copies of every gene. Every normal cell must have two normal copies of the retinoblastoma gene—Rb. To develop sporadic retinoblastoma, Knudson postulated, both copies of the gene needed to be inactivated through a mutation in each copy of the Rb gene. Hence, sporadic retinoblastoma develops at later ages because two independent mutations have to accumulate in the same cell. Children with the inherited form of retinoblastoma, in contrast, are born with a defective copy of Rb. In their cells, one gene copy is already defective, and only a single additional genetic mutation is needed before the cell senses the change and begins to divide. These children are thus predisposed to...