On Tuesday, December 17th, 2013, Dr. Janet Rowley passed away. The story of her research and life serves as inspiration to Women Scientists, Men Scientists
, Drug Developers and Urban Cyclists.
After receiving her M.D. in 1948, Dr. Rowley worked part-time through the 1950s-60s while raising four children. In 1961 she asked the director of the Argonne Cancer Research Hospital: “I have a research project started in England that I’d like to continue with. Could I work here part time? All I need is a microscope and a darkroom. And by the way, will you pay me? I must earn enough for a baby sitter.” And he said yes to everything!"
During this period she primarily worked at Karyotyping
(or examining the chromosomes and their arrangement) of the nuclear DNA associated with various cancers. Through exacting visual examination of the micrographs of the chromatids of cancer patients, she determined the molecular basis of an aberration seen consistently throughout individuals with CML (Chronic Myelogenous Leukemia). While the gross phenotype of this aberration (a shortened Chromosome 22) was originally identified in 1959 and termed the Philadelphia Chromosome
, Dr. Rowley used new fluorescent banding techniques to establish the cause of this chromosomal curtailing. In cells from 9 CML patients, she found that the missing piece of their Ch. 22 was in fact transposed to the arm of Ch. 9. Reciprocally, a small piece of Ch. 9 was now on Ch. 22.
While this finding, published in 1973, represented a previously unexplored molecular level of detail of the chromosomal phenotypes of cancer, it also provides the foundations for one of the most triumphant tales of cancer biology research and drug discovery.
In quick succession, Dr. Rowley and colleagues found other translocations associated with other Myeloid Leukemias, demonstrating that this was a more common mechanism in the etiology of leukemias and lymphomas
In the case of the CML associated 22<—>9 translocation, subsequent decades of research has identified the exact oncogenic mechanism that arises as a consequence of the chromosome arm swaps. Briefly, in the translocated Philadelphia Chromosomes, an important cell cycle regulatory tyrosine kinase
, ABL (Abelson murine leukemia viral oncogene homolog 1) that normally resides on Ch. 9, is fused to the BCR (Breakpoint Cluster Region) protein. This is not a perfect union of the two proteins, as the BCR-ABL fusion is lacking the auto-inhibitory, SH3, region of Abl. Thus uninhibited, the now constitutively active ABL kinase drives cell proliferation and genome instability in mature myeloid and progenitor cells.
With the oncogenic culprit identified by the early 90's, Drucker
and colleagues where then able to screen libraries of small molecules in the search for candidate drugs that would inhibit the activity of the BCR-Abl fusion protein. Gleevec
was discovered to be highly effective in physically blocking, and therefore inhibiting the activity of the Abl kinase domain. When given to CML patients, the drug is both incredibly effective and precise, in that it inhibits cell proliferation only in the cancerous cells carrying the fusion protein, and with drug treatment the 8 year survival rate improves to 95.2%
Thus, thanks to Dr. Rowley's important, dedicated, and above-all patient work, thousands of patient's lives have been saved, and Gleevec remains an essential gold-standard of cancer therapies.
Never one to rest on her considerable laurels (Presidential Medal of freedom, Lasker, Albany medical etc). Dr. Rowley was a fixture on the UChicago campus, running an active research program even after being diagnosed with Ovarian Cancer in late 2010.
On a bright pink bike, and always wearing a helmet, she was still making her way around the streets of Hyde Park until earlier this fall.
An admirable figure in all her parts, she will be greatly missed.