The Philadelphia Chromosome

by Jessica Wapner

  plate 12

  As Eichner was rapidly informed, danger could eventually come. If the treatments didn’t work, within five years his bone marrow would fill with blast cells, white blood cells that fail to mature and thus are both overly abundant and thoroughly useless. His blood, once free flowing, would turn into viscous sludge. The supply of iron-rich red blood cells that carry oxygen around the body would steadily plummet, leaving him fatigued and anemic, while a decrease in the number of platelets would render his blood unable to clot. As the disease moved from the accelerated phase (more than 15 percent blast cells) to blast crisis (more than 30 percent blast cells), the minuscule capillaries leading to his eyes and brain would clog. His spleen would likely become profoundly enlarged. As his body began shutting down, he would bleed in his brain, in his intestines, and out of every orifice.

  Two days later, Eichner was having his first bone marrow biopsy, performed by a nurse who spoke broken English and had to climb on top of Eichner to hammer in the four-inch-long needle to break through his bones, which had become hardened and inflamed from the profusion of white blood cells inside.

  Finally, she managed to extract an ounce of marrow, the spongy matter in the center of our bones where new blood cells are made. In the genetics laboratory, a fluorescent dye applied to the coiled strands of DNA inside Eichner’s blood cells revealed the telltale sign of CML: a genetic mutation known as the “Philadelphia chromosome,” an abnormal chromosome regarded as the defining feature of this fatal, spontaneously arising cancer and discovered more than fifty years ago. Twenty out of twenty cells in a sample of his marrow contained this genetic error.

  A family friend with the same type of cancer told Eichner to call a doctor named Brian Druker right away. “Don’t do anything before you see him,” the friend told Eichner a couple of days after his diagnosis. Three days later, Eichner got a call from Druker, who’d mysteriously—Eichner didn’t know exactly how—gotten his phone number. During the next twenty minutes, Druker talked Eichner down from his panic, assuring him that, being in the early stages of the disease, Eichner could wait a week or two before making the trip south to Oregon Health and Science University (OHSU), where Druker had been treating and researching leukemia since 1993. He gave Eichner his professional blessing to go drink beer. It was August, and Eichner had been getting ready to leave for a day at Olympia’s annual summer Brew Fest, his brother’s idea for getting his mind off leukemia for a while, when the phone rang.

  Ten days later, Eichner was on his way to Portland. Within three weeks of his diagnosis, he was swallowing his first tablet of medication, which Druker had been instrumental in developing: a drug aimed at tackling the cancer at its root.

  The first few days of treatment were pure hell. Eichner vomited several times a day, often through the night, and the nausea kept him from sleeping. As the drug flushed out the overload of blood cells that had accumulated in his marrow, the pain of his bones readjusting was excruciating. The lack of sleep and collection of medications to help his body cope with this new situation left him weak and pale. Though he continued his supervising work at the new canola oil plant his employer was building, walking the site for hours a day to ensure that the electrical work was correct, he’d be dead tired by early afternoon. Only later, when his cheeks were rosy again, did his crew confess how shockingly sick he’d looked. A visit to Eichner’s ex-wife in Colorado meant his teenage son was spared the sight of his work-hard, play-hard father curled up in pain and retching over the toilet. By the time his son returned home, the side effects were over, and Eichner was adjusting to his new reality. Though his muscles were still recovering, he was back at the gym and able to walk the construction site all day without tiring.

  NOW, IN THE chill of February, the summer before his diagnosis seemed like a dream. He was living in Vancouver now, a work relocation that brought him just twenty minutes away from OHSU. He and his wife, having put their divorce on hold when he was first diagnosed, were now legally separated. Six months after he became a cancer patient, it was time for another bone marrow biopsy to find out if the drug was working. While Eichner’s son and brother hung out at the hospital café, Druker explained to Eichner what he was looking for at this stage of treatment. The bone marrow biopsy would provide a trained technician with a sample of marrow cells—twenty of them, to be exact—to examine under a microscope. When Eichner was diagnosed, all twenty cells had the telltale genetic sign of CML. Because the cancer progressed very slowly over several years, even a minor decrease in the number of cells containing the mutant gene would satisfy Druker that the treatment was working. Thus his reassuring comment, “I will be happy if you’re eighteen out of twenty.” As Druker, his calm blue eyes matching his gentle demeanor, explained to his patient, just two fewer abnormal cells were enough to signal that the medicine was working. He told Eichner how varied the results could be at this stage. There was a chance the drug hadn’t done anything, leaving Eichner at twenty out of twenty. Or, he could be well below eighteen, even at zero.

  With his black hoodie, jeans, trim goatee, and rugged face, Eichner hardly looked like someone battling cancer. His build was stocky but trim; he’d managed to start lifting weights again, he told the nurse, though not at full throttle. He had an easy smile and a gruff, hearty voice, and he was quick to respond to both doctor and nurse, eager to impress the professionals.

  After a few more minutes spent talking about test results and the like, Druker, 56, knew the time had come. It was time for the biopsy, and he could see that his patient was nervous. “Are we done stalling?” he joked, trying to set his patient at ease. Eichner moved to the examination table, where he lay belly down, the thin white paper crumpling beneath him. A second nurse injected a dose of Ativan, a general anesthetic, into a vein in his arm, and Druker injected a shot of lidocaine, a local anesthetic, directly into his hip, where the needle would be inserted. A couple of feet away, a technician prepared the instruments, laying them out neatly on a metal table for Druker. Across the room behind a thin, floral-patterned curtain, another nurse had taken the seat by the computer, a pink streak jazzing up her blonde bob. She called out, “Gary, what’s your name and date of birth?” “Gary Eichner, 10, 5, 69,” he replied. The pain medication had started to relax him. “And what are you having done today?” she asked, following hospital protocol to confirm this information with the patient before every surgical procedure. “I’m having a bone marrow biopsy,” he said. Her reply of “good job” was greeted by a deep laugh from the rapidly numbing Eichner.

  The bright room, lit as much by the wall of windows as by the fluorescent ceiling lights, grew quiet. Small bursts of chatter among the two nurses, doctor, and lab technician at each step of the process arrived like waves onto a silent shore and quickly retreated. “You’re going to feel a needle stick back here,” Druker told his patient. “To avoid total discomfort, you have to breathe.”

  As a botanist bores into the side of a tree for a sample of the trunk’s core, so does a doctor drill into the marrow. After making an incision in the skin, Druker, his lean runner’s physique leaning over Eichner’s back, drove a slender, bevel-edged, hollow cylinder, called a trocar, enclosing a sharp needle, or stylet, straight downward. He pushed the cylinder and needle through muscle and fat toward the iliac crest, the winglike bone that forms the top of the butterfly-shaped pelvis. Though fit and strong, Druker exerted all his strength twisting the handle at the top of the trocar back and forth to break through the bone. He leaned on Eichner for leverage, feeling the first tingles of perspiration as he continued to push downward.

  It was this effort that had Eichner’s nurse at his first biopsy calling for a hammer. Still stinging from that memory, Eichner was prepared for the worst, but Druker, his necktie tucked inside his checked shirt to avoid tickling his patient’s flesh, worked quietly and efficiently. Any words he uttered were strictly to comfort his patient. Eichner’s bones had softened now that he’d had the drug in him for six months, and
it took Druker just a couple of minutes to get the needle inside Eichner’s left hip bone.

  Standing on the other side of the bed, monitoring the Ativan dose, a nurse asked Eichner every minute or so how he was doing. Leaving the needle sticking out vertically from the top of Eichner’s buttocks, Druker unscrewed the stylet and inserted a syringe through the trocar. First was the “dry pull,” an extraction of 1 or 2 milliliters of marrow. With this sample, a technician would check the size and shape of the cells, and the percentage of blasts. A second syringe drew about 10 milliliters of marrow; this one was the “wet pull,” with heparin added to stop the blood cells from clotting. This sample would be sent to the genetics lab where, in a darkened room, technicians would count the number of cells housing the Philadelphia chromosome. If it were twenty out of twenty, the drug was not working—not yet, anyway. Anything less than twenty would satisfy Druker. Eichner was holding out hope for zero.

  Druker completed the two pulls, handing over the samples of marrow, red like blood but shinier, to the technician, who verified the source of the specimen by the presence of spicules, white clumps interspersed throughout the body’s marrow. Last was the bone biopsy. Druker inserted a new needle and dug farther into the hip bone. He removed the stylet and turned the trocar back and forth, shaking loose a bit of bone that remained stuck inside the cylinder. Druker pulled the stainless steel tube out of his patient’s body and knocked the centimeter-long piece of bone into a small plastic canister.

  Eichner’s son, lanky and tall, with floppy hair and warm brown eyes, and his brother, slightly older than Eichner but with the same casual air, returned from the café soon after the procedure was complete, quickly displacing the awkwardness of the moment with mild teasing about Eichner’s exposed bottom. It was the first time they’d met Druker, a moment that Eichner had been hoping for when he asked his son to join him on the trip. Eichner flipped over, woozy and slightly silly from the anesthetic. He buttoned his jeans and exchanged some parting words with his doctor.

  The hole in Eichner’s bone would take about two weeks to heal. The test results would be ready in about three weeks. In the best-case scenario—no cells containing the Philadelphia chromosome—this bone marrow biopsy would be Eichner’s last, possibly for the rest of his life.

  THREE WEEKS AFTER his biopsy, Druker’s words were still bouncing around Eichner’s head. “I will be happy if you’re eighteen out of twenty.” Eichner knew that he, too, should be happy with that, because that would mean he was responding to his medicine. It would mean he could keep going with the pills he’d grown accustomed to, but with no more experiments, no need to put his body through the wringer with a new drug. It would mean that he was safe. Just that much of a reduction would be enough to confirm that the cancer inside his bones was not going to kill him.

  On March 6, 2012, Eichner received an e-mail telling him that his test results could be viewed on MyChart, the private online system that enables patients to access their medical records remotely. Before he had a chance to read them, Carolyn Blasdel, Eichner’s main contact at Druker’s clinic and the same nurse who’d questioned him about side effects, had left messages on his answering machine about the results. “She called me a couple of times, one after another, so I knew something was going on,” said Eichner, who thought he heard a positive tone in her voice on the messages she’d left.

  He’d seen some initial findings from his last visit. His white and red blood cell counts and some other information had been posted on MyChart just a few days after the biopsy. But he couldn’t make much sense of the numbers. He thought they looked good, but what did he know? Plus, he didn’t want to give himself false hope. The only number that mattered to him was how many out of those twenty sampled cells still contained the Philadelphia chromosome.

  He called Blasdel from work, and she reviewed all the tests with him, explaining the meaning of words like FISH, karyotype, and Bcr/Abl. She opened up the cytogenetics report on her monitor and read the key phrases to him. “All twenty metaphase cells appeared normal male. All results were within the normal limits,” the report stated. She translated the words into plain English: None of the analyzed cells had the Philadelphia chromosome. He was zero out of twenty. There was, Blasdel read to him, “no morphologic evidence of chronic myelogenous leukemia.” And, his white blood cell counts had returned to normal.

  Because the data on patients who’ve taken the medicine Eichner was taking are still evolving, clinicians now deliver prognoses to CML patients in five-year intervals. Based on the response rates so far, Blasdel explained to Eichner, he had a 99 percent chance of surviving the next five years.

  Surrounded by coworkers and $20 million worth of electrical equipment at his job site, Eichner tried to contain his joy. “You just want to scream and go crazy,” he said. As good as it felt to finally tell the news to someone at work, the best moment came a few hours later, “letting my son know when I got home that night that the next five years are good.” Eichner would be there for his son for at least a few more years. He knew how lucky he was. “Ten years ago, I’d be almost dead right now,” he said. “Now I have a five-year [outlook] that is almost a guarantee, as long as I take my medicine.”

  Three months later, Eichner got more good news. The latest tests showed that he was in complete molecular remission. The most probing analysis had revealed no evidence of abnormal cells. Although he couldn’t be considered cured, since the disease would likely recur if he stopped taking the pills, the remission meant that Eichner was, for the foreseeable future, essentially cancer free.

  PART I

  The Chromosome and the Disease

  1959–1990

  • • •

  In 1959, the blood-based cancer known as chronic myeloid leukemia (CML) was universally fatal. Even when the disease was diagnosed in its earliest stages, most patients died within six years. The sole treatment, radiotherapy for the spleen, did little to improve the odds. Several decades later, treatments were still inadequate: Drugs gave many patients an extra few years, but eventually the malignancy became unmanageable.

  CML was hardly exceptional. Even in the early 1980s, nearly every type of cancer remained stubbornly incurable. Those who treated it stumbled into a hopeless vortex, and almost all who had it faced an early death.

  1

  _______

  THE FIRST CLUE

  David Hungerford could not believe what he was seeing.

  He hovered over a microscope, turning the wheels this way and that to ensure the best view. A small glass slide was illuminated from below. It held a single cell that had been expanded and then stopped in the middle of reproducing, its forty-six chromosomes on full display. He checked and rechecked, and was absolutely certain: One of the chromosomes was too short.

  It was 1959, and the field of genetic research was almost nonexistent. The 1956 confirmation of the standard number of chromosomes housed in the human cell—forty-six, in twenty-three pairs, one set inherited from each parent—hinted at something impossible to grasp, a continent on a horizon too distant to see with the tools of the day. Even though James Watson and Francis Crick had made their famous discovery of the helical structure of DNA in 1953 and the genetic root of Down syndrome—an extra copy of one chromosome—had been found the same year, the search for connections between DNA and disease had only just begun. Around the world, laboratories were just starting to toy with the kind of technology needed to explore genetic matter. Genes were units of heredity, a way for traits to be passed on from one generation to the next, including deficiencies. But how disease could possibly be linked to DNA was entirely unknown. Phrases like “genetic mutation” or “chromosomal abnormality” were not part of the vernacular yet because there was no need for such language.

  And so it was that David Hungerford, a young scientist hovering over a microscope, was stunned by what he was seeing through the lenses. This was a man who knew how chromosomes should look. Camera-equipped microscopes were hot laboratory comm
odities in the 1950s, and Hungerford, an avid photographer, had gotten a job working with one in a Philadelphia cancer research center. He spent countless hours looking at the starfish-shaped chromosomes of the drosophila fly, training his eyes to see the fine banding patterns within. He was one of a handful of people alive at the time who could have spotted an anomaly among a blurry, inky array of chromosomes.

  plate 1

  So it may have been inevitable that he’d ended up working with Peter Nowell, a doctor also in his early thirties doing cancer research across town at the University of Pennsylvania. In 1956, Nowell had accidentally stumbled upon a new method for seeing chromosomes inside cells. He had been studying blood cells from leukemia patients, his work following the usual approach of the day: rinsing the cells and staining them with a bluish-purple dye.

  Science had come a long way in its ability to peer inside cells, the basic structural units inside every living thing, since they were first spotted by microscope in 1665. That discovery led to others, which led to the creation of cell theory, the notion that all living things are made of cells, and that new cells are made when old cells divide. But the cutting-edge techniques for seeing the inner clockwork were still rudimentary, calling for the scientist to squash a drop of cells on a covered glass slide with the thumb in order to put pressure on the cells. The squash was supposed to burst the cell, spilling out its gene-filled middle. But the approach failed as often as it succeeded, leaving behind broken cell fragments that were useless to researchers. People were frustrated with the technique, which wasted precious time and resources.

  One day Nowell took a shortcut around the usual scientific procedure. “Pete was in a hurry, as young men tend to be,” Alice Hungerford, David’s wife, would recount years later. Instead of following a more rigorous cleaning method, Nowell washed a sample of white blood cells under some tap water. He dropped the rinsed cells onto the slide and was amazed by what he saw through the microscope. The tap water, it turned out, was hypotonic—a low-pressure solution that caused the cells to swell, like a deflated raft being blown up with too much air.