Jessica Wapner - The Philadelphia chromosome: a mutant gene and the quest to cure cancer at the genetic level

FOREWORD

BY ROBERT A. WEINBERG, PHD

A widespread illusion is that cancer is a disease of modernity, an artifact of pollution and bad diet and myriad other factors associated with a modern lifestyle. The truth is quite different: The disease of cancer threatens all multicellular life with greater or lesser frequency. In the case of our own species, cancer incidence has exploded because we now live long enough to develop a diseasemuch like Alzheimersthat largely strikes the aged.

Until recently, we did not know how and why the disease arose, and yet, in spite of this, we developed the means to treat somebut hardly allforms of the disease. The use of chemotherapy and radiation has had a remarkable effect in treating some cancers and almost no effect on others. By the early 1970s, however, it was already clear that these cytotoxic therapies had yielded almost as much benefit as they possibly could; that is, they had exhausted their potential for making major inroads into reducing cancer-associated mortality. Those looking over the scientific horizon concluded that new ways of treating the disease were required.

The thinking of those interested in such innovations in cancer treatment focused on how the disease was being caused. If only one could understand the defects within cancer cells, they reasoned, novel ways of treating the disease would surely emerge. This article of faith gained currency with the discoveries in the second half of the 1970s that distinct cancer-causing genes could be found within cancer cells. The genessoon called oncogenesappeared to be the motive forces behind the runaway proliferation of many types of human cancer cells. By attacking these genes (and more specifically, the proteins that they produced), highly targeted, extremely effective therapies could be developed, or so the thinking went.

The proponents of this new approach to dealing with cancer portrayed their strategy as a means of developing anticancer drugs rationally, by focusing on specific molecular defects within cancer cells. They contrasted this new way of treating cancer with the traditional strategies involving cytotoxic treatments, which were portrayed as blunt, crude instruments that had been used with limited success for the previous several decades. The latter therapies had been developed without any knowledge whatsoever of why cancer cells behaved aberrantly. For the first time, the prospect was bright; by attacking malfunctioning proteins within cancer cells, tumors as a whole could be brought to their knees.

By the early 1980s, the research into the molecular origins of cancer began an explosive growth, and by the end of the century we had amassed a truly extraordinary body of detailed information on why cancer cells proliferate abnormally. Translating these results into novel treatments, however, has not come so easily. There have been the usual scientific obstacles of developing drugs that could strike the cancer cells with great specificity, selectively killing those cells while leaving their normal counterparts relatively unaffected. Such selectivity in targeting cancer cells is rarely absolute; almost always, side-effect toxicities attend even the most successful targeted therapies. Then there were the economic considerations, specifically, whether the rapidly growing cost of developing novel anticancer therapeutics could ever be recouped through clinical drug treatments.

The Philadelphia Chromosome