Cancer Research Pioneer Dr. Alfred Knudson Dies at 93

His insights into the genetics of hereditary cancers broke new ground

Alfred Knudson

It’s perhaps tough to imagine, but decades ago scientists had little inkling that parents might pass down abnormal DNA that upped the odds for a particular cancer in their child. Or that cells might have mechanisms to help defend themselves against these aberrant, cancer-linked genes.

That all changed when Alfred Knudson, MD, PhD, decided in the late 1960s to investigate what are now known as heritable cancers. 

Knudson worked for 40 years at Fox Chase Cancer Center in Philadelphia and passed away in July at the age of 93. But, early in his career, he was intrigued by a rare eye cancer called retinoblastoma.

Doctors had long known that the tumor could run in families, even striking newborns. Knudson, a pediatrician by training, understood that, because retinoblastoma could strike children so young, environmental factors weren’t likely to play a major role. The key to the disease must instead lie in genetics.

Investigating further, he presented convincing evidence in a 1971 paper for what is now known as the “two-hit” theory of heritable cancers.

In essence, the hypothesis postulates that a child may receive a damaged (or mutated) gene from one parent, but on its own that is not enough to spur cancer. 

However, a “second hit” may occur – an environmental insult, for example – that tips affected cells towards tumor development. 

But for the two-hit theory to work, Knudson theorized there must be something “holding back” the initial, aberrant gene from causing cancer on its own.

This notion helped speed the discovery of what are now called tumor-suppressor genes – DNA that helps put the brakes on cancer.

The disabling of such genes is now known to be a major stepping-stone to tumor development.

In essence, Knudson “provided the conceptual framework for how we think about cancer now,”

Dr. Jonathan Chernoff, chief scientific officer at Fox Chase, told The New York Times at the time of Knudson’s death.

The “two-hit” theory was given added proof in 1986 when scientists elucidated the gene (Rb1) and mutations leading to heritable retinoblastomas. The same approach has now been used to better understand other cancers, such as the BRCA1 gene that can help trigger breast tumors.

Knudson was born in 1922 in Los Angeles. He received his bachelor of science from the California Institute of Technology and his medical degree from Columbia University. He returned to Caltech to earn a PhD in biochemistry and genetics in 1956.

In an interview with the Lasker Foundation, he said he was attracted to genetics because it, “was unique at that time among the biological sciences because it had a precision about it that wasn’t customary in biology.”

Speaking to the Washington Post, Joseph Testa, a scholar of human genetics at Fox Chase, said that Knudson had “ideal training. He was perfectly suited to make such a discovery that was over the head of just about any other person who was thinking about cancer at that time.”

Knudson began his work at the MD Anderson Cancer Center and the University of Texas Graduate School of Biomedical Sciences, in Houston. But the bulk of his career was spent at Fox Chase, where he had served as president, scientific director and in other roles.

Knudson received many awards and accolades, including a 1998 Lasker Award, commonly known as the American Nobel, and a 2004 Kyoto Prize recognizing him for a discovery that, “opened a new horizon in modern cancer genetics and played a pivotal role in the major developments” in cancer research.

Knudson is survived by his wife Dr. Anna Meadows, who is also profiled in this issue. Dr. Meadows enjoyed a distinguished career as a cancer researcher in pediatric oncology at the Children’s Hospital of Philadelphia.