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DCEG Mourns the Loss of Alfred Knudson, Friend, Mentor, and Author of the “Two-hit” Theory of Carcinogenesis

Dr. Knudson sitting in a laboratory

Dr. Alfred Knudson

Alfred G. Knudson, Jr., M.D., Ph.D., was a visionary geneticist best known for his groundbreaking theory of cancer causation that explained the relationship between hereditary and non-hereditary forms of cancer, and paved the way for the eventual discovery of tumor-suppressor genes. Published in 1971, his “two-hit” mutational model was derived from an elegant mathematical analysis of the clinical and epidemiological patterns of the pediatric eye tumor, retinoblastoma; he reported that one germinal and one somatic mutation were responsible for hereditary cases, and two somatic mutations for non-hereditary (sporadic) cases. Dr. Knudson was then able to map the chromosomal location of the retinoblastoma gene, which provided the basis for its isolation by others as the first known tumor-suppressor gene (RB-1).

Dr. Knudson came to the NCI on leave from the Fox Chase Cancer Center in the late 1990s to help the leadership of NCI develop the research agenda in cancer genetics across the Institute and its newly formed Division of Cancer Epidemiology and Genetics (DCEG). It was an exhilarating time in cancer genetics and biology, and Dr. Knudson agreed to serve for several years as acting director of the DCEG Human Genetics Program. Dr. Joseph F. Fraumeni, Jr., the founding director of DCEG, commented that “Al’s extraordinary scientific insights and mentoring were critical to accelerating progress during the early years of the Division."

Writing in a commentary in The Linkage newsletter in 1998, Dr. Knudson described his approach to research as open-ended: “The largest advances in science often come when you least expect them. When you specify everything you’re going to do in a plan, it tends to diminish opportunities for major breakthroughs.”

Dr. Robert Hoover reflected on his friend and colleague, “what impressed me most was the depth and breadth of Al’s intelligence—it wasn’t limited to his scientific training. He was brilliant on any topic he took interest in.”

According to Dr. Fraumeni, “Al’s scientific stature and his interdisciplinary approach to cancer research helped build bridges between basic, clinical and population sciences that fueled collaborations across NCI and well beyond.”

Dr. Knudson has been recognized with the most prestigious scientific awards and honors that are given in biomedical research. Here at NCI, the Alfred G. Knudson, Jr. Award Lecture was established in 1998 to recognize visionary thinkers in the field of cancer genetics. For almost two decades, Dr. Knudson attended the lectures and poster sessions given at the annual NCI Intramural Scientific Retreat, even after he returned to Fox Chase. He was always accompanied by his wife, Dr. Anna Meadows, a leading pediatric oncologist who had also taken leave from the Children’s Hospital of Philadelphia to direct the first NCI research program in cancer survivorship.

As successor to Dr. Knudson in directing the human genetics program in DCEG, Dr. Margaret Tucker emphasized that Dr. Knudson’s impact was felt beyond his seminal discoveries in cancer research. “Al was an unfailingly kind and generous friend and mentor who inspired the careers and enriched the lives of all who came into contact with him. We will always remember him as a hero in medicine.”