Alfred G Knudson

BMJ 2016; 354 doi: (Published 09 September 2016) Cite this as: BMJ 2016;354:i4862
  1. Ned Stafford
  1. Hamburg
  1. ns{at}

Pioneer of cancer genetics who developed the groundbreaking “two hit” hypothesis

As a teenager growing up in Los Angeles in the late 1930s, Alfred G Knudson loved physics, chemistry, and mathematics. Biology did not interest him much. When he enrolled at the California Institute of Technology (Caltech) in 1940, he thought he was taking his first big step towards becoming a physicist. He was wrong.

Owing to factors that were mostly beyond his control, Knudson ended up seven years later as a paediatrician. He would spend the next two decades—except for a three year sabbatical to earn a doctorate in biochemistry—as a practising paediatrician, focusing on cancer treatment. But while caring for sick children with the kind heart of a physician, the scientist within him could not stop pondering the question: “How do children develop cancer?” He was determined to discover the answer.

“Two hit” hypothesis

He intensified his search for the answer in 1969 after moving to the University of Texas MD Anderson Cancer Center in Houston as a professor and as dean of the graduate school of biomedical sciences. He chose to focus his research on retinoblastoma, a rare cancer already known at the time to have a hereditary form.

He had access to detailed records of children treated for retinoblastoma, and—having learned from his study of physics to always strive for “simple explanations”—he felt that as the cancer could be found “even in a newborn child” then it must “be as simple as cancer can be.”

He conducted his study by using a combination of genetics, mathematical analysis …

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