The Philadelphia Chromosome by Jessica Wapner

- Ethan Cerami

As scientists, we spend most of our time asking, “what’s next?”, “what’s new?”. We rarely spend enough time looking backward to learn or appreciate how we got here in the first place. In the field of targeted cancer therapy, Jessica Wapner’s Philadelphia Chromosome offers us all a chance to look back, and to marvel at the enormous progress in cancer research over just the past fifty years.

Ostensibly, the “Philadelphia Chromosome” is about the development of Gleevec, the blockbuster drug developed by Novartis for treating Chronic myelogenous leukemia (CML). As such, the book attempts to trace the scientific threads connecting the initial discovery of the Philadelphia Chromosome in CML patients in 1959 to the clinical development of Gleevec in the 1990s. But, in doing so, it traces the full historical arc of modern cancer research: the discovery of oncogenes by Michael Bishop and Harold Varmus, the identification of BCR/ABL as the gene fusion caused by the Philadelphia Chromosome, the discovery of protein kinases, the creation of cell lines, the development of kinase inhibitors, and even the development of resistance to targeted cancer therapies. With thorough research and clear writing, Wapner traces each of these scientific threads, explaining how disparate fields of research combined to conquer CML. In describing the early research on CML and cancer oncogenes, and in one of my favorite passages of the book, she writes:

The way the Philadelphia chromosome led to CML was a story that unfolded like a hundred painters applying brushes to a canvas at some time or another over twenty five years… There’d been no final picture in mind and no awareness that they were event painting something together. And yet, there it was. A scientific masterpiece.

Wapner also provides a human face to the heroes of CML, with particular attention to David Hungerford and Peter Nowell, who in 1959, made the initial discovery of the Philadelphia Chromosome, and Janet Rowley, who discovered in 1973 that the Philadelphia Chromosome was in fact a translocation between chromosomes 9 and 22. Particular attention is also payed to Brian Druker, Nicholas Lydon, Alex Matter, and Charles Sawyers, all of whom played pivotal roles in the development of Gleevec or second generation CML drugs. Druker receives the top-billing, though, and it’s clear that patients and patient advocates believe that Druker is the true hero of Gleevec. Originally called STI-571 in clinical trials, many patients were disappointed with the name Gleevec, and several even suggested it be renamed “Drukercillin”. Another patient praises Druker to no end, claiming that Druker is “right up there, right under God.”

As the story of Gleevec unfolds, Novartis receives some criticism for not moving quickly enough with clinical trials, and even greater criticism for the cost of Gleevec, but, Wapner’s treatment of Novartis is even-handed, and the company gets more than enough credit for bringing Gleevec to market in the first place. There are therefore no really evil protagonists in this story, no high-stakes drama between the stakeholders, and most of the central characters appear quite rational and sane, and all arrive at the right conclusions in the end.

As such, one could argue that the Philadelphia Chromosome lacks a dramatic arc, but the book is absolutely riveting, because it deals with life and death of real people, and this is where the book truly shines. Before Gleevec, Wapner describes the fate of patients with CML – a horrifying disease which was “universally fatal”. Describing Gary Eichner, a patient diagnosed with CML in Chapter 1, Wapner describes what would have befell him prior to Gleevec: “his blood, once free flowing would turn into viscous sludge… as his body began shutting down, he would bleed into his brain, in his intestines, and out of every orifice.” Wapner also does an excellent job of describing the horrible side effects of interferon, the standard of care before Gleevec, with it’s attendant fevers, chills, “paralyzing fatigue”, and depression – taking interferon could be “like having a flu that lasts for months or even years at a time”.

While today’s world of targeted therapies usually considers a modest 3-6 extra months of life a success, it is still astounding to consider that many patients from the initial clinical trials for Gleevec are still alive today. As Druker marvels at one point during the clinical trials of Gleevec: “the problem I was having was that it was too good to be true. If I told you I could give you a pill that was going to put your cancer in remission with no side effects, would you believe it?”. It is still hard to believe, and as Robert Weinberg of MIT points out in his foreword, Gleevec remains the “poster child” for rational drug development, which has been “followed disappointingly, by few comparable success stories.” Nonetheless, the story of Gleevec is one of unmitigated triumph, and remains a beacon of hope for everyone in cancer research. Wapner’s book does justice to this story, and one can only hope that future cancer drug development will be chronicled as effectively.

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