The Philadelphia Chromosome Quotes

“was able to report that the compound was potent, selective, and cellularly active. The final molecular formula was C29H31N7O • CH4SO3. Described another way, its designation was 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate. It was a white to off-white to brownish powder with a molecular mass of 589.7; it also carried the weight of forty-three years of science history. The compound was named CGP-57148B. “To me,” said Buchdunger, “it was already quite a little bit of a miracle.”
― Jessica Wapner, The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment

“A man named George Daley, yet another member of the Baltimore lab, had finally accomplished this remaining feat. Daley took one group of mice and filled their marrow with the mutant bcr/abl gene present in the Philadelphia chromosome. Next, he destroyed the bone marrow of a second group of mice with radiation. He injected the second group of mice with the marrow from the first group, and the second group of mice developed CML. The experiment established the mutant chromosome, and therefore its protein product, Bcr/Abl, as the sole cause of CML. The proof bolstered Lydon’s belief that the kinase program at Ciba-Geigy should make Abl its top priority. Despite his and Druker’s conviction that Bcr/Abl was the best target for proving the principle of kinase inhibition, the program had”
― Jessica Wapner, The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment

“rather than the usual milligrams—to be practicable. The body cannot handle such high quantities of a powerful chemical; and even if that were not the case, the administration of a ridiculously large pill or lengthy infusion would be impossible, even parceled out over a day. But having seen that the chemical did something, the team deemed this the “lead” compound, the one it should focus on. Lead in hand, the chemists had to find a way to improve it. Adding a molecule called 3’-pyridyl to the original chemical scaffolding heightened its activity. With the introduction of a single six-sided molecule, suddenly Buchdunger could see that the compound was blocking PKC with much greater efficiency. Next the chemists added a benzamide group, a molecule created by exposing a version of benzoyl (a component of the acne-fighting combination benzoyl”
― Jessica Wapner, The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment

“atom, which another atom with an abundance of electrons would stick to as if with glue. Some molecules dissolved in fat rather than water. Inside an oily environment, two chemicals might join together, though such bonds were usually weak. For Zimmermann, these hidden worlds held endless possibilities. Combining molecules together in various ways had led to the creation of plastic, of countless medications, of every synthetic substance. The manmade world was made of chemistry. So was the natural world, for that matter. Surely, Zimmermann thought, there was a way to manipulate some molecules into a kinase-inhibiting drug. The challenge lay in more than creating the perfect shape. To be a good inhibitor, the compound also had to stick to the kinase. Creating that”
― Jessica Wapner, The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment

“Several molecules had already shown some anti-kinase activity (albeit with the coarse profiling tools available at the time). There was the isoquinolinesulfonamide from Hidaka’s work. A group from Japan found that a molecule they named erbstatin inhibited EGFR. A group in Israel, led by Yosef Graziani, showed that quercetin, part of a naturally occurring group of chemicals known as flavones, also affected kinase activity inside some tumor cells. The same had been seen with some isoflavones, which also occurred naturally. And there was staurosporine, the antifungal agent that Levitzki had been exploring as an inhibitor of PKC. The fatal flaw of that compound had been its lack of specificity. Could it be adjusted in a way that led it to one kinase, and one kinase only, inside the cell? The next task was to actually make”
― Jessica Wapner, The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment

“PDGFR, or Bcr/Abl. Their strategy was to focus on the exact place on the kinase that bound phosphate on its way from ATP to the protein. The theory behind kinase inhibition was that each kinase had a particular notch or groove that made a tight fit with ATP, and that the shape of these notches varied from kinase to kinase. That variation was what made kinases viable drug targets. Zimmermann believed that this binding site—the exact spot where the kinase bound ATP to capture the phosphate that would be used to switch on another protein—seemed like the most likely location of each kinase’s unique fingerprint. That binding site was what allowed the kinase to serve its function on the cell, so it made sense to Zimmermann that this area would be distinct both from the binding site of other kinases and from other areas on the same kinase.”
― Jessica Wapner, The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment

“whether to become a professor or join a pharmaceutical company. He’d grown frustrated doing experiments simply as an academic exercise. Molecules that he and his fellow researchers had synthesized would be thrown away without being tested for any potential application, the sole goal being to prove that the structure they’d created was the one they’d intended to create. “I always protested,” he recalled. “Wouldn’t it be nice to synthesize something that could be [useful]?” After all, that was what he’d loved about chemistry in the first place: You make something. Just as Lydon had gravitated toward the practicality of kinase research, Zimmermann wanted to be in a place where he could put that urge for application to good use. He opted to return to Ciba-Geigy, joining the oncology group. Alex Matter opened Zimmermann’s”
― Jessica Wapner, The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment

“The chemists at Ciba-Geigy began churning out compound after compound. They weren’t drugs yet; that title could be awarded only after the compound was known to effect some change in the body, not just in a culture of enzymes. During this stage of searching for hits, the chemicals were compounds, candidates, or, if they showed hints of anti-kinase activity, agents. And Matter zealously pushed the chemists to come up with more and more of them, a pressure”
― Jessica Wapner, The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment

“Still, for the moment he was keeping quiet about his interest in cancer. “You have to realize, cancer was a devastating disease,” said Druker. “Everybody died.” The disease was a grim, dark domain where only the most morbid physician dared tread, and Druker was unwilling to admit, even to himself, that he was fascinated by it. “Everybody was afraid of it, and people in oncology [were] weird because this disease was so hopeless,” he recalled. “Why would you go take care of patients with no hope? You were crazy if you were going to do that.”
― Jessica Wapner, The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment