Peter C. Nowell (1928-2016).

The pioneering cancer cytogeneticist, Peter C. Nowell, died on December 26, 2016, from complications of Alzheimer’s disease at the age of 88. His work laid the foundation for the recognition of the genetic basis of cancer that paved the way for modern targeted cancer therapeutics. Nowell’s observations of changes in chromosomal anatomy during progression of malignancies led him to predict that it was the accumulation of genetic abnormalities that underlies cancer progression, predating notions such as genomic instability as a fundamental hallmark of cancer. Nowell was born on February 8, 1928, in Philadelphia. He attended Wesleyan University as an undergraduate and medical school at the University of Pennsylvania, graduating in 1952. He then performed a rotating internship at Philadelphia General Hospital and trained in pathology at Philadelphia’s Presbyterian Hospital. Nowell was drafted into the military and spent 2 years studying the health effects of radiation at the Naval Radiological Defense Laboratory in San Francisco, before joining the faculty at the University of Pennsylvania in 1956, where he stayed for the remainder of his career. As a pathologist, Nowell’s primary tool for discovery was the light microscope. He contributed to development of methods for visualizing chromosomes in mitotic cells (karyotyping). In 1960, using his improved karyotyping methods, Nowell and his associate David Hungerford published their discovery of the first nonrandom chromosomal alteration in cancer: an abnormally small chromosome #22 that was present in all blood or marrow samples from patients with chronic myeloid leukemia (CML) (1). In the seminal paper describing this finding, Nowell wrote that this discovery suggested a causal relationship between the chromosomal abnormality observed and CML. This notion was met with great skepticism, but his prescient prediction was confirmed by numerous subsequent discoveries. This included Janet Rowley’s work showing that this shortened chromosome 22, now called the Philadelphia (Ph) chromosome after the city in which it had been discovered, resulted from a reciprocal exchange of genetic material between chromosomes #9 and #22. This chromosomal rearrangement generates a fusion gene BCR-ABL, which encodes an activated tyrosine kinase. Befitting the seminal discovery of the Ph chromosome as the first cytogenetic abnormality in cancer, the first kinase inhibitor to be approved by the Food and Drug Administration and other health authorities for cancer treatment was imatinib mesylate (Gleevec), an oral small-molecule inhibitor of the BCR-ABL kinase that has transformed outcomes for patients with CML. Before imatinib, the median survival of patients with CML was typically 3 to 5 years; now the majority of patients achieve durable remissions and have a near normal life-expectancy. Nowell’s observations on cytogenetic changes with tumor progression were profound, giving rise to the hypothesis that cancers begin with a small number of Portrait of Peter C. Nowell. Image courtesy of the University of Pennsylvania Art Collection.