Alfred George Knudson

Abstract

Paediatrician and cancer geneticist. He was born in Los Angeles, CA, USA, on Aug 9, 1922, and died in Philadelphia, PA, USA, on July 10, 2016, aged 93 years. It's around 25 years since Jonathan Chernoff went to Fox Chase Cancer Center in Philadelphia, PA, USA, for a job interview. The man in charge of recruitment was Alfred Knudson, an ex-director of Fox Chase and already renowned for having devised the hugely influential “two hit theory” to account for the relation between inherited and spontaneous tumours in certain types of cancer. Chernoff, then a young postdoctoral researcher but nowadays Deputy Director of Fox Chase and its Chief Scientific Officer, well remembers being disconcerted that Knudson, a very much older man, refused to allow him to carry his own suitcase. Equally surprising was Knudson's office. “You'd think this would have been some grand room with a nice view. In fact it was in the basement, a windowless hole in the wall.” Chernoff uses this to illustrate what he and others see as the central feature of Knudson's personality: his humility and total lack of any self-aggrandisement. One of Knudson's colleagues at Fox Chase summarises the measure of what the man had in fact achieved. “I consider him the father of hereditary cancer genetics”, says Professor Joseph Testa, Director of Fox Chase's Clinical Cytogenomics Laboratory. “His elegant mathematical models were deeply conceptual and sometimes hard to understand, but he could explain it in ways that all of us could follow.” Knudson's two hit theory grew out of thinking about the childhood cancer retinoblastoma. He focused on childhood cancer because he reasoned that the younger you were, the fewer the number of non-inherited mutations your genetic material would have accumulated. He then noted that where retinoblastoma ran in the family, children tended to get the disease early and bilaterally. By contrast, children in whom it wasn't inherited tended to be older and get it only in one eye. “He couldn't have been the first to observe this”, says Chernoff, “but he was the first to think about it in a different way…he started to run some equations and came up with the simplest model…This would be if there were two alleles controlling things, and the inheriting families would already have one mutation so all they needed was one more to get a cancer.” Members of non-inheriting families would have to get not one but two mutations: a much rarer event. Knudson was predicting the existence of what we now refer to as tumour suppressor genes. Definitive proof of their existence had to wait for the development of the necessary technology, another 15 years. Many more tumour suppressor genes have since been identified. “They all follow the same general rules that Al laid out”, says Chernoff. “The theoretical framework has held up very well.” Knudson's work brought him many honours including, in 1998, the Albert Lasker Clinical Medical Research Award. Knudson began his career with a science degree from the California Institute of Technology (Caltech). “He had a keen mathematical mind”, says another Fox Chase colleague, Professor Alfonso Bellacosa who works on cancer epigenetics. “Originally he was thinking of studying physics…but then he came to the realisation that in physics a lot was already known, so he switched to biology instead.” Knudson moved to Columbia University to study medicine, specialised in paediatrics, graduated in 1947, and returned to Caltech to work for a doctoral degree, choosing genetics as the field most likely to offer opportunities to exploit his mathematical interests. After jobs at the State University of New York at Stony Brook and the University of Texas Health Science Center he eventually joined Fox Chase as its Director in 1976. “He always believed that studying rare tumours and hereditary cancer would later give us an understanding of more common sporadic cancers that dominate the field”, says Testa. “He spent a lot of time thinking deeply about his work.” Chernoff echoes that comment: “Al did not do a lot of experimental work in his life. I never saw him with a pipette and test tubes in his hands.” Knudson's ideas ran ahead of his colleagues' capacity to collect the evidence that would eventually test and prove them correct. Those ideas had a profound influence on the careers of many of his junior colleagues, and on the direction of cancer research itself. “He was extremely caring and gentle”, says Bellacosa. He was a very clever and well informed man with many interests but who wore his learning lightly. Knudson leaves a wife, Anna, three daughters by a first marriage, and three stepchildren.