Leading Edge
Obituary Riley, Kansas. He was always, at heart, a physician and defined himself as a ‘‘pediatrician in an Army uniform’’; in two An iconic, visionary giant in medical sci- he had established the famous ‘‘Fly years, he cared for 1,500 newborn chilence, Alfred G. Knudson, Jr., M.D., Ph.D. Room.’’ Harbingers of Al’s bright future dren and young adults on the base. Since died July 10, 2016, one month short of in medicine, Caltech professors Morgan, ‘‘science was passing him by,’’ he rehis 94th birthday. Often referred to as the Linus Pauling, and Carl Anderson (discov- turned to Caltech to earn a Ph.D. in ‘‘Mendel of cancer genetics’’—Al was erer of the positron) wrote recommenda- biochemistry and genetics in 1956. widely known for his groundbreaking tion letters for Al. Knudson’s first academic position was ‘‘two-hit’’ hypothesis of cancer developAl was in medical school at the time at the City of Hope Medical Center, ment and his prediction of recessive- DNA was being discovered as the genetic Duarte, where he led a pediatric cancer acting tumor suppressor genes. His revo- material by Oswald Avery and colleagues, unit and biology department. During lutionary two-hit hypothesis envisaged across town at the Rockefeller Institute, 1966–1969, he was Associate Dean for that cancer occurs when both copies of but students never learned of this; later, Basic Sciences at the State University of such a gene sustain mutations. The first Al emphasized that medical students New York, Stony Brook. He moved to hit may be hereditary, and the second should be up on basic science, as one M.D. Anderson Cancer Center in Housoccurs somatically. This theory, originally never knows where the next medical ton, where, using the detailed records of based on studies of hereditary and nonhe- breakthrough will come from. He decided children treated for retinoblastoma, he reditary forms of retinoblastoma, was later to do a residency in pediatrics at New developed his two-hit theory and became shown to be applicable to many cancers. York Hospital because pediatrics would Dean of the Graduate School of BiomedHis elegant mathematical models, bor- allow him to combine genetics and devel- ical Sciences. In 1976, he joined Fox rowed from physics and probability opmental biology. During his residency, a Chase Cancer Center in Philadelphia, theory, served as the foundation for month spent at Memorial Sloan Kettering where he held positions of Director of understanding the relationship between Cancer Center provided a life-changing the Institute for Cancer Research and hereditary and sporadic cancers. Proof experience working in a small unit of President, although his greatest acaof his prescient ideas took more than a about 20 children with cancer, most of demic pleasure was that of senior investidecade, with the emergence of recombi- whom would not survive to leave the gator working with younger colleagues. At nant DNA technologies that permitted hospital. Fox Chase, he established the Molecular validation of the model by Webster During the Korean War, Al was in the Oncology Program, later defined by David Cavenee and colleagues and subsequent Army as a ‘‘payback’’ for the support he Livingston as the ‘‘left ventricle of the cloning of the first tumor-suppressor had received by the Navy to attend med- Center,’’ to which he recruited many new gene, RB1, by Stephen Friend and ical school and was stationed at Fort colleagues, including the authors. colleagues. In 1976, Al married his secBorn in Los Angeles, Knudond wife, Anna Meadows, a son entered Caltech—very petite, energetic, and driven near the Glendale section pediatric oncologist at Chilwhere he lived—in 1940. He dren’s Hospital of Philafirst intended to study physics delphia. Anna, who was but soon thought that much interested in eye-sparing treatwas already known in that ment for retinoblastoma, told field and turned to biology, him that she fell in love with especially genetics, due to his two-hit paper before she its foundation in mathefell in love with him. In return, matics, a discipline for which Al defined Anna as a ‘‘worthy he had a keen interest. His opponent’’ with whom he passion for genetics was discussed ideas and revised fueled by training with the talks and papers prior to legendary Thomas Hunt Morpublication. Together, they gan and Alfred Sturtevant. published articles on retinoAl wanted to obtain a Ph.D., blastoma and neuroblastoma but because of WWII, deand formed a sort of dialectic cided to join the Navy as it but loving ‘‘good cop-bad could support his training as cop’’ couple that animated a physician. Morgan thought the scientific, medical, and that there were no good medsocial life of Philadelphia. ical schools in California at Al never officially retired, rethat time and suggested taining titles of Distinguished Drs. Meadows and Knudson at a fundraising gala in Philadelphia in 2005. Image courtesy of Children’s Hospital of Philadelphia. Columbia University, where Scientist and Senior Advisor
Alfred G. Knudson (1922–2016)
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to the President. He and his colleagues at Fox Chase identified a germline mutation of the tuberous sclerosis 2 tumor suppressor gene, Tsc2, as the genetic determinant of renal carcinoma in the Eker rat. His continued love of physics and mathematics was reflected in collaborations with Michael Vilenchik on mutagenesis by ionizing radiation, rates of induction of single- and double-strand DNA breaks, and implications for tumorigenesis. Finally, over the last decade, his team worked closely to characterize gene expression changes in one-hit cells from genetically susceptible persons, for cancer prevention. Among his numerous awards, Al received the Charles Mott Prize from the General Motors Cancer Research Foundation (1988), the Medal of Honor from the American Cancer Society (1989), the Gairdner International Award (1997), the Albert Lasker Award for Clinical Medical Research (with Janet Rowley and Peter Nowell; 1998), the Distinguished Career Award from the American Society of Pediatric Hematology/Oncology (1999), the Kyoto Prize (2004), and the AACR Lifetime Achievement Award (2005). He was elected member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the American Philosophical Society and was an inaugural Fellow of the AACR Academy (2013). He also served as President of the American Society of Human Genetics (1978). On a personal level, Al was a charming and caring person. Despite his largerthan-life, charismatic scientific stature, he remained humble, open, and approachable. He had a profound influence on the welfare of Fox Chase. His career at this institution was marked by his boundless intellectual curiosity, generous mentorship, gentle collegiality, and selfless dedication to scientific progress, as well as being an inspirational role model for younger scientists privileged to work with him. He conveyed an unwavering passion and excitement for science. He was, quite simply, the perfect mentor. Al’s talent extended beyond his own work. In 1979, in his role as Scientific Director, he was approached by his Fox Chase colleague Ernie Rose regarding the possibility of providing institutional
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support for two young Israeli scientists— Avram Hershko and Aaron Ciechanover—on the mechanism of ubiquitin-mediated protein degradation. Al immediately recognized this project as having enormous implications, and as an opportunity for a team with unique drive and skillset to solve it. Support was duly provided and the rest, as they say, is history, culminating in the Nobel Prize being awarded to this team in 2004. In 2002, Fox Chase celebrated Al’s 80th birthday. A poster signed by staff in honor of the occasion repeatedly cited his inspirational leadership, insightful and magnanimous mentorship, ability to focus on the true essence of a scientific problem, as well as his scientific curiosity balanced not only by a desire to help colleagues with their research, but also by a genuine interest in their personal welfare. In 2003, a special issue of Genes, Chromosomes & Cancer celebrated Al’s legacy with a collection of historical perspectives and reviews. Included in the collection was a memoir written by Al, ‘‘Cancer Genetics Through a Personal Retrospectroscope,’’ in which he humbly credited the help of colleagues and trainees, including Ed Lewis, Jim Neel, Louise Strong, Anna Meadows, George Klein, Harry Harris, and David Commings. Reciprocally, essays by others highlighted life-changing, pivotal moments when Al helped shape the research direction of oncology and genetics fellows, such as Anna Meadows, who defined Al as ‘‘my best friend and colleague and the love of my life’’ and Stephen Friend, who called Al ‘‘a visionary who enables scientists.’’ Al was always generous with his time and extraordinarily supportive of young people. He advised them to give more consideration to important things over urgent things and to be strategic and selective in the laboratory, stating that ‘‘the best scientists are the ones knowing which experiments not to do.’’ Al balanced his research life with passionate interests in art, music, and travel. Anna Meadows noted that she ‘‘learned much from Al about astronomy, geology, history, art and music, and always with humor.’’ Together, they had a strong appreciation of both figurative and abstract art, and their home was filled
with an eclectic and colorful collection of paintings and sculptures. Al knew the ‘‘K’’ number of every Mozart piece, and his travel diaries were written with the precision of a scientific paper: in a pretracking devices era, he plotted by hand changes in distance and elevation of every excursion, adding historical notes and interesting bits of information about various locales. He was fascinated by discovery and was content with the trajectory of his life: ‘‘I have a great life, because I’m interested in things that aren’t known yet.’’ Looking back at the amazing, unimaginable accomplishments in science over his lifetime, Al noted: ‘‘We had some good years together at Fox Chase. They were the best years for me, in terms of liking the people I worked with, the things we got done, and the response to our work.’’ Al aged gracefully and with great dignity. In the last year, he told us, with his gentle chuckle, that his mind was failing but accepted that realization with wisdom, expressing it with his characteristic clarity: ‘‘It’s sad to be losing your mind, but I tried to think back about my life and what I would do differently, and it turns out I probably wouldn’t change anything, because I wound up doing something that was useful, important in some circles, and I enjoyed doing it, so what more can you ask for?’’ To those of us fortunate enough to have had the opportunity to know Al personally, the passing of this mentor and friend is a great loss. Up to his final days, he continued to work on his scientific manuscripts and care greatly for the welfare of scientists at Fox Chase and everywhere. His visionary work and the generation of scientists worldwide who continue the pursuit of his passion for cancer genetics are a lasting legacy.
Alfonso Bellacosa,1,2,* Jonathan Chernoff,2 and Joseph R. Testa2,* 1Cancer
Epigenetics Program Biology Program Fox Chase Cancer Center, Philadelphia, PA 19111, USA *Correspondence: Alfonso.Bellacosa@fccc. edu (A.B.),
[email protected] (J.R.T.) http://dx.doi.org/10.1016/j.cell.2016.07.052 2Cancer
