The Philadelphia Chromosome

by Jessica Wapner

  Cancer proved to be an efficient teacher. A senior colleague insisted that Druker ask for help when he needed it but added that after three months he’d be so familiar with the treatments he wouldn’t need to ask anymore. “That was absolutely true,” he said. He immersed himself in reading about cancer drugs, learning what tests to use to tell if a treatment was working, and diagnosing each specific type of cancer. His patient roster included Dana-Farber trustees and inner-city drug addicts.

  Then came John Bullitt, who taught English at Harvard University and had been diagnosed with lung cancer after decades of chain smoking. The gruff professor took a shine to Druker right away. On the day that Druker explained the diagnosis and treatment to Bullitt, the attending physician—who had to sign off on the work of first-year fellows like Druker—was one renowned both for his breast cancer expertise and his huge ego. He introduced himself pompously to Bullitt and talked casually about his treatment, which he really knew nothing about, and then left abruptly. Bullitt saw right through his act. As soon as the door closed, he turned to Druker and said, “He is full of shit.” Bullitt had recognized the doctor in Druker, and hadn’t needed reassurance from another. In that moment Druker finally allowed himself to become a doctor. “I’m okay, I’m a doctor,” Druker remembers realizing. “I’m going to be an oncologist.” According to the medical license authorities, he’d already become a doctor. Now he’d become one on his own authority.

  That first year had more to teach Druker. If he was to come to terms with being a cancer doctor, then he had to learn to cope with death. Most of his patients would die, if not shortly after coming under his care, then in the easily foreseeable future. That was what happened with cancer: Almost everyone died from the disease. So he learned to temper his expectations about what he could do, reasoning that if he could add a few months of quality time, that was a good enough goal. He learned that unless his patient had Hodgkin’s disease (a type of blood cancer) or testicular cancer, the only curable cancers at the time, he or she would die. “You have to face that fact, and you have to protect yourself a little bit,” said Druker. He learned to talk to the families of his dying patients, especially after the harshly worded letter one family wrote to Dana-Farber after Druker sided with an end-stage patient who had decided against further treatment. He took up the institute’s tradition of writing to the families whose loved ones had died under his care, and he attended funerals of the patients with whom he’d been closest. Dana-Farber’s practice was to allow the fellows to continue treating their choice of forty or so patients as they headed off to their laboratory training after the first year of their fellowship. By the end of that second year, Druker was left with about five patients, and by his third, perhaps one or two, as each one succumbed to cancer.

  In 1985, in the thick of his first year, his schedule still filled with patient care, it was time to choose a lab. “In sort of typical fashion, I had no clue,” says Druker. He was engraved with David Kipnis’s advice to pursue oncogenes, but he had no idea how to choose a lab where he could do that. He heard from a friend about Tom Roberts, an up-and-coming young doctor at Dana-Farber who was studying oncogenes. “So I went and talked to Tom,” says Druker, “and he was talking this language I didn’t understand.”

  That foreign language was, of course, the language of laboratory research. Roberts was a PhD scientist who’d followed a straightforward path to lab research, unlike Druker. Years earlier, Druker’s lab research had brought him on an unconventional course toward medical school. Now he was circling back to the lab by way of medical school, another path less taken. So when Druker asked if he could join the lab, Roberts wasn’t sure. His response—“I’ve never taken a medical oncology fellow before”—exemplified the chasm between the laboratory and the clinic that has pervaded medicine until only recently. Druker insisted that he could get his own funding, that it wouldn’t cost Roberts a dime to have him there, and so Roberts agreed.

  From there, Druker plunged straight down to the bottom of the ladder. Here he was, a board-certified internal medicine specialist coming off a year of intense oncology training, and he knew absolutely nothing about laboratory research. He struggled to get through articles on the latest oncogenes research. Every day he was surrounded by people who seemed to know exactly what they were doing, and he was completely clueless. Taking care of dying lung cancer patients looked simple from his new vantage point.

  To be fair, the world of oncogenes had become vast and complex since Bishop and Varmus had first announced the cellular origin of the src oncogene. Their discovery still stands as a landmark moment in the history of cancer research. Now, the study of these cancer-inducing genes had taken on a life of its own, separate from the study of cancer-causing viruses. In the late 1970s and early 1980s, Robert Weinberg, yet another eminent scientist just down the hall from David Baltimore’s lab at MIT, along with Michael Wigler of Cold Spring Harbor Laboratory and Mariano Barbacid of the National Cancer Institute, independently reported genes they’d found in the DNA of tumor cells that, when extracted from those tumor cells, could transform normal cells into cancer cells in culture. These oncogenes had nothing to do with oncogenes found in retroviruses like the Rous sarcoma virus and the Abelson virus, yet in many cases they were proving to be extraordinarily similar.

  Before 1975, cancer could not be understood in terms of genetics because cells couldn’t be studied at that level. From 1975 to 1985, the landscape of cancer had become more detailed. It was like moving from the broad strokes of Matisse to the pointillism of Seurat. As researchers like Weinberg were uncovering how genes transformed from proto-onco to onco—through mutations caused by carcinogens, for example—the world at large was beginning to see cancer through gene-tinted glasses.

  A cancer doctor now becoming a cancer scientist in the mid-1980s, Druker personified that shift and its accompanying brain-scrambling struggles. Not only was he without basic research skills, he was without any knowledge of the field. He had no idea what kinases were. He had no idea about the Abelson virus, or src, or chromosomal translocations. “Now there’s a history to molecular biology and cancer research,” said Druker. “At that time, there wasn’t any history.”

  In the mid 1980s, many geneticists believed that there would ultimately be about 100 oncogenes found among the total complement of human genes. And, Druker and others were being told, genes with cancer-causing potential would probably all be ones that were highly conserved; that is, they’d been around for a long time. Highly conserved genes are the ones found in vast numbers of different species, indicating their importance throughout evolutionary history. It’s like a chef who has used the first knife she bought for cooking school to make ever more complicated dishes; that knife is highly conserved.

  Unlike Naomi Rosenberg and Herb Abelson, whose contributions to the Philadelphia chromosome story were directly related to the freedom they were given to pursue their ideas, Druker’s research career began in the opposite trajectory. Clueless as he was about the laboratory, he needed a concrete project that would serve as an introductory course. Roberts assigned him to study polyomavirus, which causes tumors in rodents. It was the same virus that had led Tony Hunter to his discovery that tyrosine, a rare and unexplored amino acid, served as the binding site—the landing platform—for the phosphate delivered by the kinase. Roberts wanted Druker to lay out the cascade of events that led from infection to cancer transformation.

  For scientists interested in oncogenes, polyoma had a significant advantage over many other cancer-inducing viruses. The revelation delivered by Bishop and Varmus about src was that it originated not in the virus but in healthy mammal cells. The oncogene version of src, the one that expressed an abnormal kinase, was just slightly different from the proto-oncogene version, the one that existed in healthy cells that expressed a normal kinase. Their similarity made them tricky candidates for biochemical experiments because it’s hard for researchers to be sure which version they’re dealing with at any given m
oment, like telling the difference between identical twins at first introduction. By contrast, the oncogene in polyomavirus doesn’t have a normal, proto-oncogene counterpart. As an only child, it was a much easier biochemical system with which to work.

  Druker proceeded with no clear idea of where the work would lead him. The world of cancer research was not wondering about the relevance of such work to human cancer. “Nobody cared about that,” says Druker. “People didn’t talk about translation to the clinic.” Today, terms like “bench to bedside” and “translational research” signify the growing pressure for scientists to aim their work toward a practical result with some tangible benefit—for the microscopic world of research to have more immediate relevance to the macroscopic world of human suffering. But at that time, the lab and the hospital were distinct worlds, and scientists and doctors did not view themselves as aligned to a common goal. Clinical faculty like Druker who entered lab research were considered as good as gone, an attitude with some foundation. “You [had] people who went into the lab and did their research, and nothing ever came out,” says Druker. “It was just this big, black hole that you’d send people into, and you’d just never see them again.” As he began to fiddle with the microscopes and test tubes around him, Druker wondered if he was heading toward the same fate.

  His job was to unravel the so-called signal transduction pathway by which polyomavirus caused cells to become cancerous. He would break down the hundreds of amino acids in the virus into blocks of fifty or fewer, to see which increasingly small group held the secret to the cancer transformation. If he mutated these ten amino acids, does the tumor still occur? Just as Sir Philip Cohen’s pioneering research had done with insulin at Dundee, Druker was trying to piece together the stream of signals launched by the kinase, like a relay race in which the gene shoots the gun and the kinase is the first runner. Roberts and Druker were trying to trace the baton from the starting line to the finish line.

  The work was grueling, essentially requiring Druker to make mutations of around 500 amino acids, one at a time. And the information the research yielded was slow in coming. “It got me a lot of training,” said Druker, “but didn’t get me a lot of actual publications.” The discoveries he made turned out to be more internal, more personal development than cancer development. Over the course of the five years he spent on the project, he learned what it was to be an academic lab researcher. He’d become a doctor, on paper and in thought. Now, he was becoming a scientist.

  TWO YEARS INTO the fellowship, Druker was working in the lab on a weekend, doing a routine preparation, cutting and pasting genes and trying to figure out whether they recombined correctly. The work had become automatic for him, leaving his mind free. On this particular day, he started questioning what he was even doing in the lab. Why had he gone to medical school? Why had he done the intense residency only to get entrenched in basic research? He still believed the lab work would lead him somewhere, but he missed seeing patients and worried about losing touch with medical care. “Someday I may want to do something that benefits patients,” Druker remembers thinking. “But how can I do that if I’ve lost those skills?”

  His discontent was well timed. A position was opening up at Nashoba Community Hospital, in Ayer, Massachusetts, a town not far from Boston. The job, medical director of the oncology clinic, would require just one day a week of patient care. The arrangement was ideal: Druker could keep his connection with patients and spend the other six days at the lab (taking days off was not something that occurred to him).

  A nebulous goal began to form in his mind. He knew that his urge to continue treating patients was for a specific purpose. “Somebody might figure something out, and I might want to run a clinical trial,” he said. “I wanted to be part of that.” He was a good doctor who’d seen the inadequacy of cancer treatments time and time again. Now, for the first time, he began to articulate why he had ended up in the laboratory after medical school, and why that had driven him back to the clinic: If molecular biology discovered how cancer begins and progresses, he wanted to help convert that knowledge into something that would improve the lives of patients.

  Following close on the heels of that decision came his first significant contribution to cancer research. In the late 1980s, a woman named Deborah Morrison, who had expertise in making monoclonal antibodies, joined the Roberts lab. She possessed the same skills that Owen Witte had brought to the Baltimore lab a decade earlier, creating antibodies to tease out proteins. Druker knew that if he were to run his own lab someday, he’d need to know how to make antibodies for specific proteins, and he took the opportunity to learn all that he could about it from this new researcher.

  The best way to learn the technique was to just go ahead and do it. He decided to make one for phosphorylated tyrosine, using mice as the antibody-producing animal. Druker was aware that research was pointing to tyrosine phosphorylation as a general mechanism driving cancer. Tyrosine was the surprising amino acid to which the kinase encoded by src bound phosphate, the bit of energy that powered up the protein and appeared in other signaling pathways that started with a kinase and resulted in cancer. Witte had discovered that Bcr/Abl, the fusion protein that induced CML, was a tyrosine kinase, but Druker wasn’t thinking solely about CML. He just knew that tyrosine was emerging as an important substance in cancer research.

  By the late 1980s, he was also hearing murmurs about the possibility of creating drugs that could block the tyrosine kinase as a way to stop the progression of cancer. If a cancer resulted from the haywire activity of an abnormal tyrosine kinase—as seemed to be the case with Bcr/Abl—then could cancer be stopped by somehow turning off the kinase, by halting it in its tracks? Kill the kinase and you kill the cancer, the theory went. Around the world, a handful of experiments were showing that theory might just pan out.

  The antibody Druker was trying to create could be an invaluable research tool, he knew, because it would show how much tyrosine had been phosphorylated. An antibody against phosphotyrosine—the shortened way of referring to phosphorylated tyrosine—would automatically latch onto the substance, as antibodies do to foreign invaders. That attack would draw the target protein away from the rest of a cell’s contents, enabling it to be measured. If a drug inhibited the tyrosine kinase, then the amount of phosphotyrosine in drug-treated cells would be less than in untreated cells. And if the amount indeed decreased in a drug-treated sample, then the drug was doing something—at the very least, it was blocking the kinase from its phosphate-carrying work. In theory, that inhibition would prevent the protein at the top of the cancer-causing cascade from being switched on. If the incessant signal from the kinase to produce white blood cells never came, then cancer wouldn’t develop.

  Those thoughts, however, were vague and distant in Druker’s mind as he struggled over two years to make the antibody. His goal was only to learn how to make the antibody. But although the two years of efforts taught him how to do it, he was having no luck getting a final product: Every attempt was a failure. Finally, the lab contracted the work out, and it soon had its antibody, called 4G10, to phosphorylated tyrosine. From there, Druker could grow the clone, purify it, and experiment with it. But the primary mission had already been accomplished: He had acquired the skill. “It may be useful someday,” he thought at the time. As it turned out, the work he had done was about to come in very handy, but not in the way he anticipated.

  There was one other unexpected consequence of his work on 4G10. In 1988, the other lab member working on the project with him introduced Druker to her roommate, Barbara. She and Druker began dating, and two years later they were married.

  15

  _______

  TURNING A PROTEIN INTO A DRUG TARGET

  In the early 1980s, back when Druker was just starting to learn basic laboratory research and nursing the shrunken ego that came with returning to the bottom of the ladder, Nick Lydon, the man who’d skulked the halls outside Phil Cohen’s lab at Dundee to gather whatever he could
about kinases, was already gripped by the possibility of creating drugs to block the cancer-causing enzymes.

  And he wasn’t the only one. His boss, Alex Matter, had also lit on the idea. Matter had a brief clinical career before entering pharmaceutical research. Though Matter’s work as a bedside oncologist had been brief, it was enough to leave him haunted about the state of cancer treatment. “[It] was an absolutely earth-shattering experience,” said Matter, who’d been devastated by the death of one of his patients, a young mother with ovarian cancer who’d left behind three children. His degree of helplessness was equally upsetting. “There was nothing that I could actually do about it,” he said. He decided to move into industry. A job focused on making better drugs seemed more worthwhile than treating patients with the available medications.

  In the late 1970s, Matter took a job at Roche Pharmaceuticals, where a colleague talked about new ideas that were starting to enter the drug development arena, including the possibility of stimulating the immune system as a way to eradicate cancer, or forcing cancer cells to age and die off using substances derived from vitamin A. Matter had some success developing drugs at Roche, but never for any serious cancers. The breakthrough he’d been hoping for eluded him.

  A few years after joining Roche, Matter moved to Schering-Plough, where Lydon had gone after Dundee, as head of oncology drug development. The company had just acquired a drug called interferon, a synthetic version of a substance that occurs naturally in the body. Interferon stimulates the immune system, and for Matter it was the first exciting drug of his career. In some instances, the drug could eradicate cancer. Interferon turned out not to be the panacea that many researchers had predicted it would be, but it did work in several different types of cancer, including melanoma, a type of leukemia called hairy cell leukemia, and also CML. (Interferon’s greatest benefit turned out to be in the treatment of viral infections; it was the standard treatment for hepatitis C until only recently.)