In 1959 David Hungerford at the Institute for Cancer Research at Fox Chase saw an unusually short chromosome 22 in patients with chronic myelogenous leukemia. Forty-two years later, Gleevec (imatinib), a drug specifically designed to target the unique genetic lesion, was approved by the FDA. The epic of this long and winding road is the topic of Jessica Wapner's engaging book, The Philadelphia Chromosome.
Wapner is an accomplished science writer who has written for Scientific American, The New York Times, Slate, and Nature Medicine, among others. She has employed the required scientific rigor to tell this story with both accuracy and elegance.
As with research in general, the path is a complex maze of "shoots and ladders" that frequently bedevils scientific and medical discoveries. For anyone who wonders why progress takes so long, this book provides many of the all-too-common answers.
After Peter Nowell and Hungerford made their initial observations in the 1960s, it was another 10 years before the next major advance. The field lay fallow, not because of any loss of interest, but because better techniques for chromosomal study were not available. Progress had to wait for chromosomal banding to be developed. This empowered Janet Rowley in the 1970s to use the technology to show that the genetic alteration in CML was a translocation. The missing piece of chromosome 22 was stuck onto chromosome 9. But still nothing was known about how this alteration actually caused cancer.
Before scientists could understand how this genetic translocation actually caused cancer, it required another decade of work on the cellular origin of oncogenes and the recognition that the gene products of many of these genes were kinases. It was not until 1990 that George Daley in David Baltimore's laboratory showed that the mutant chromosome and its protein product Bcr/Abl was the actual cause of CML.
If the exact cause of CML was known in 1990, why were 11 more years required to identify and approve an effective treatment? Again, Wapner deftly and thoroughly explores a vastly different set of obstacles and challenges in the clinical development of the drug. She describes the complicated search for agents to target the defective kinases. She notes the disruption caused by the timing of the merger of Sandoz and Ciba-Geigy.
Another major obstacle was the struggle of Brian Druker and Nick Lydon to generate any interest in a drug for a rare disease like CML. Once interest had finally piqued and a potential drug identified, there were further interruptions resulting from conflicting animal toxicology and difficulties compounding the oral medication.
Fits & Starts
These fits and starts make for lively and entertaining reading. Unfortunately they are frustrating to scientists and clinicians and frightening to patients, who understandingly are anxious to have successful therapies for serious diseases sooner rather than later.
But the tale of The Philadelphia Chromosome is not an outlier. The reality is that many medical discoveries have a similar timeline of long periods of intermittent progress followed by explosions of productivity. It is hard to envision how this can be altered dramatically. As Wapner points out, "methods were invented for a need that had never existed." Most of the major participants in this discovery process interviewed by the author acknowledge that some work could have moved faster, but in the main there were no preventable major impediments.
The latter portion of the book bursts with the early optimism of the clinical trials and the controversies surrounding who should lead them. Wapner chronicles the rise of patient advocacy and the impact of Internet communication on the clinical trials process. Finally she explores the scuffles surrounding how to distribute credit for the discoveries. As Alex Matter, one of the champions of the drug's development at Novartis, said, "Victory has a lot of fathers."
Transformational discoveries by definition change everything in ways difficult to foresee. One major hurtle to the drug's development was the lukewarm interest in any drug for a very rare disease. The marketing arm of Novartis in the late 1990s predicted that the peak sales would likely be $100 million. But no one inside or outside Novartis had forecast long years of successful treatment for CML patients. Nor did they anticipate expanded use of the drug for other diseases like GIST, myelodysplasias, and systemic mastocytosis and others that harbored the same aberrant protein target.
As a result, sales in 2002 were $900 million and by 2007 rose to $2.5 billion yearly.
Appealing to the Appropriate Audience
The challenge for a book like The Philadelphia Chromosome is to appeal to the appropriate audience. Most, if not all practicing oncologists already know both the science behind this discovery and the clinical success of Gleevec and the drugs to circumvent resistance which followed. From the public's perspective, CML is not a common cancer like breast cancer, and the typical reader has probably heard more about targeted or personalized therapy than about one of its best examples-CML and Gleevec.
None the less, the saga is well told here and provides both oncologists and the public insights into the realities of scientific research. The book illustrates the importance of undirected research, with the major contributions of Hungerford, Herbert Abelson, and Naomi Rosenberg, who were not following any predefined path but were simply "driven by curiosity."
Wapner highlights the importance of sustained financial stability to allow science to flourish. She also illustrates how critical the seemingly mundane technical advancements were to the subsequent critical scientific discoveries.
Generally Wapner deals with complex science and medicine skillfully. Occasionally there are slipups, such as "Multiple Myeloma targeting the plasma, hardening the fluid into tumors inside the marrow," or confusing a leukemic thrombosis with an aneurism. These however are small medical miscues that detract little from the overall narrative.
In The Philadelphia Chromosome Wapner has captured the erratic and episodic nature of scientific and medical discovery through the lens of one of the most transformational discoveries in oncology of our time. For that reason, the book should find its way onto the booklists of lay audiences who seek to better understand how science actually works. And, for those involved in cancer research, it is a well-known story, but one that is comprehensively covered in this well-crafted book.
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2013, THE EXPERIMENT LLC, HARDCOVER, 320 PAGES, ISBN 1615190678; ALSO AVAILABLE IN KINDLE AND AUDIO EDITIONS