One can hardly open an issue of Cancer Research without finding a half-dozen or more articles that address the role of various tumor suppressor genes in cancer. We now take it for granted that cancer is, at its core, a genetic disease and that one of the most important ways that mutations in DNA induce malignant transformation is through damage to both alleles of tumor suppressor genes. Although many scientists over many decades contributed to building this model, its chief architect was Alfred G. Knudson, Jr, MD, PhD.
When Knudson died at 94 on July 10, 2016, the field of cancer genetics lost one of its true giants. With tools no more sophisticated than pencil and paper, he proposed a quantitative mechanism to explain how inherited damage to genes could lead to cancer. First formalized as the “two-hit” theory in 1971, this idea remains perhaps the single most influential paradigm in all of cancer genetics, essential for understanding the origins of hereditary and sporadic malignancies. In terms of its simplicity, power, and influence, his work can justly be compared with that of the 19th century geneticist Gregor Mendel, whose famous pea garden in Brno was a must-see pilgrimage site when Knudson visited Czechoslovakia in the 1970s.
During his youth, Knudson had a strong interest in and knowledge of mathematics and physics, and these interests served him well when he later turned to genetics. His college years at the California Institute of Technology (Pasadena, CA) no doubt spurred his interest in this area, as he encountered professors such as Thomas Hunt Morgan, Alfred Sturtevant, and Linus Pauling and began a lifelong friendship with Ed Lewis, who was a graduate student at that time. He then received his MD from Columbia University (New York, NY) and, key to all that followed, subsequently did a residency in pediatrics at New York Hospital (New York, NY) that included a stint at the pediatric unit of the Memorial Sloan Kettering Cancer Center (New York, NY). He continued his clinical work in pediatrics at an Army Base during the Korean War, returning to the California Institute of Technology for his PhD.
After an initial faculty appointment at the City of Hope Medical Center in California, Knudson became the Associate Dean for Basic Sciences at the State University of New York at Stony Brook Health Sciences Center (Stony Brook, NY). In 1969, he moved to M.D. Anderson Cancer Center (Houston, TX), and it was there, while serving as Dean of the Graduate School of Biomedical Sciences, that he developed his revolutionary ideas about heritable cancers. In 1976, he joined Fox Chase Cancer Center in Philadelphia, PA, where he held the positions of Director of the Institute for Cancer Research and Center President.
Knudson would have thrived in any academic environment, but he made an inspired choice by coming to Fox Chase, where he had daily contact with an extremely talented group of colleagues that included, among others, Barry Blumberg, Jenny Glusker, Bea Mintz, Bob Perry, Ernie Rose, and Anne Skalka. Even among that rarefied group, many considered Knudson primus inter pares. Presenting a seminar to an audience that included such esteemed scientists could be a formidable challenge, but his gentle nature ensured that even the greenest investigator was treated as a scientific equal. The nature of his enquiry was deep and the questions he posed required careful thought, often prompting new lines of research.
Regarding his scientific legacy, Knudson was first and foremost a pediatrician, and he viewed the cancer genetics problem though the lens of pediatric cancers, in particular, the hereditary cancer syndromes. His insights that led to the two-hit theory did not require a single laboratory-based experiment, but were instead derived from an analysis of patient records, the age of onset of retinoblastoma, and the extent of disease in hereditary versus sporadic cases. From these clinical records, he deduced that children with heritable cases of retinoblastoma must have been born with a mutation in one allele of a gene that normally restrains cell growth and/or survival, and that, in such children, only one additional “hit” to the remaining allele would be required to initiate tumor formation. Sporadic cases were not hereditary because two mutations in such growth-restraining genes were required in a somatic cell. Others had previously proposed various models to explain multistage mechanisms for carcinogenesis, but Knudson's two-hit theory differed in that it provided a quantitative method by which one could infer underlying processes of tumor incidence and progression and that, at least in retinoblastoma, only two mutations were required to breach the barriers for tumorigenesis.
The theory proved such a success that it is today nearly impossible to discuss cancer in the absence of the framework provided by the now-famous Knudson two-hit hypothesis. However, what seems obvious and intuitive now was hardly the case in the late 1960s and early 1970s, when various inherited cancer syndromes were recognized but their genetic mechanisms not understood. It took several of Knudson's special gifts—a talent and interest in mathematics, an intense interest in pediatric cancers (in which he correctly assumed the mutational load would be lower than in adult cancers), and a deep understanding of genetics—to formulate the two-hit hypothesis, as well as the patience to wait the nearly 15 years it would take for cloning techniques to evolve to the point that it became possible to isolate actual tumor suppressor genes, or “anti-oncogenes,” as he initially called them. Fittingly, the first of these to be mapped and cloned was the Rb gene, whose existence and behavior he had postulated in 1971. It and the dozens of tumor suppressor genes that were cloned soon thereafter, for the most part, behaved just as he had predicted they would. Damage to both alleles was required to fully disable the brakes on cancer cell growth.
For these achievements, Knudson received many of the most prestigious awards in Biology, including, among many others, the Lasker Prize, the Kyoto Prize, and the General Motors Prize. Had a Nobel Prize in Medicine been awarded for the discovery of tumor suppressor genes, as it someday surely will be, there is little doubt that he would have won that too.
Knudson was the quintessential “big picture” scientist, with a rare talent for distilling scientific problems to their essence. For example, he had a lifelong interest in the phakomatosis syndromes and was convinced that these were fundamentally linked at the molecular level and that, eventually, we would be able to place all the proteins encoded by these genes into a single, comprehensive wiring diagram that explained the pathophysiology of these syndromes. Thus, it was with great pleasure that he lived to see the cloning of the tumor suppressor genes that are lost in von Hippel–Lindau (VHL), tuberous sclerosis (TSC), Cowden disease, neurofibromatosis I, and Peutz–Jeghers syndrome, and how their gene products interact with one another in cells. The construction of a “grand unification theory” for the tumor suppressor genes so engrossed him that it was the rare conversation about science that did not eventually turn to this weighty subject. And, drum roll please, his intuition was again correct: Many of the tumor suppressor gene-encoded proteins involved in the phakomatosis syndromes are indeed linked in a signaling pathway that explains certain common features of these disorders.
Although best known for his work on cancer genetic theory, now enshrined in standard textbooks on the topic, Knudson also had success in the experimental realm. For example, with his colleagues Ray Yeung and Joe Testa at Fox Chase, he was able to identity a germline loss-of-function mutation in the Tsc2 gene as the cause of hereditary renal cell carcinoma in the Eker rat model. Also, toward the end of his career, he assembled a team to examine how gene expression changes in cells from at-risk family members who had inherited one-hit damage to the VHL or TSC tumor suppressor genes. This work resulted in his final publication, published in Oncotarget just months before his death, with Knudson as the senior author.
Knudson's influence extended beyond his direct contributions to science. He held high-level administrative positions for most of his career and was perforce no stranger to the hurly-burly of academic politics, but he was a most unusual bureaucrat. His oft-stated motto was that he cared far more about “ideas per square foot” than “dollars per square foot,” and he meant what he said. If one had a sufficient quantity of the former, the latter was deemed relatively unimportant and he would find a way to assist in funding. Indeed, in one well-known incident, recounted in his obituary in the NY Times on July 14, 2016, Knudson's prescient support was critical in assembling the 3-man team that discovered the ubiquitin pathway for protein destruction. In this case, he asked the Fox Chase financial director for the princely sum of $50,000 to be set aside to support the salaries of Hershko and Ciechanover during their sabbatical in Rose's laboratory in 1979, because their work “will surely have great implications for developmental process, for normal physiology, and for cell death and cancer. The implications are enormous …” As in many other areas, his instincts in this case were correct, and this team went on to win the Nobel Prize in 2004.
No tribute to Knudson would be complete without the mention of a loving partner in his work, his wife Dr. Anna Meadows. Renowned in her own right for her contributions to pediatric cancer survivorship, Meadows was an intellectual foil against whom Knudson could test his ideas, and she was not afraid to challenge them. She remained a constant source of support through the many years of their marriage, and she joined him in his extra-scientific cultural interests of art, music, and travel.
Al will be sorely missed by his colleagues at Fox Chase, his friends and family, and by the scientific community at large. The many scientists and physicians whose lives he influenced will continue to carry out his legacy for many years to come.
- Received December 27, 2016.
- Accepted December 27, 2016.
- ©2017 American Association for Cancer Research.