To tell the story in “The Philadelphia Chromosome,” Jessica Wapner has to go back in time and re-create the laboratory challenges of the 1970s and ’80s. These eras are not so long ago chronologically, but the changes in genetic understanding and laboratory techniques in the intervening years mean that it can be tricky to evoke the magnitude of creative but laborious steps undertaken back when.
In 1959, David Hungerford, a scientist examining the chromosomes of a patient with chronic myeloid leukemia (CML), noticed that one of those chromosomes had an abnormally short arm. Something was missing. Remember that this was happening only six years after the structure of DNA had been discovered; the field of modern genetics was just taking shape. CML was a disease without a treatment, a slow-growing cancer of the white blood cells that could lurk for a long time in a person’s bone marrow and eventually develop into a “blast crisis,” in which abnormal white blood cells proliferate, wiping out the bone marrow and eventually killing the patient.
This book tells the story of the complex research steps that led scientists from the observation of that abnormal chromosome in CML patients to the understanding of oncogenes, genes that transform normal cells into cancer cells, and then the steps toward the development of a pharmacologic cure. Wapner uses the details of this scientific journey to illuminate many different sides of the story of research and medicine over the past three or four decades: The highs and lows of research in progress, the sociology of organized science, the politics and economics of drug development and drug testing, and the bedside challenge of caring for patients, especially when they are taking part in a clinical trial.
The characters in “The Philadelphia Chromosome” include the scientists and the doctors who were drawn into this project following Hungerford’s discovery — in particularBrian Druker, who started his fellowship in oncology in the mid-1980s. “Most of his patients would die, if not shortly after coming under his care, then in the easily foreseeable future,” Wapner writes. “That was what happened with cancer: Almost everyone died from the disease.”
Druker started as a lab researcher at a moment when the genetic understanding of cancer was developing rapidly and new therapies were beginning to seem plausible — therapies that might alter those fatal outcomes.
The chromosome abnormality had led to the understanding of a genetic deviance, a different stretch of DNA found in the cells of people with CML. But what did that different gene encode? Again, a question that might be answered quickly and easily in today’s world of rapid sequencing took arduous research — which helped elucidate not only the specific protein involved here, an enzyme called a tyrosine kinase, but also some of the mechanisms underlying cancer. The challenge was to use that understanding to create a drug that would interfere with this specific kinase and block this specific cancer.
The scientists found a possible compound — a possible treatment. But then a new process of research and investigation had to begin, obedient to a new set of rules and constraints, since this time the goal was to experiment on people. Wapner is particularly good at evoking the promise and tension of the drug trials, as STI-571 is tested in rats, mice and dogs — and the researchers and the drug company have to deal with the news that it causes liver damage in both rats and dogs.
But if the book attends carefully to the extraordinary work of the scientists, it also pays attention to that first brave — and lucky — cohort of patients who not only volunteered to test a possibly dangerous drug, but organized themselves to demand a voice in their treatment, creating an online petition to the drug company to produce more of the experimental medication and speed up clinical trials. Or as one patient put it, “There is no way that there is a drug out there that can help me that’s not going to be given to me.”
Wapner’s challenge as she turns a close eye on this complex chain of discovery, drug development and medical practice is to link the huge conceptual and experimental jumps to the details of the science. To follow the story, you have to care not only about the scientists and the patients, but also about the compound, which almost becomes a character itself: “From a genetic mutation to its haywire fusion protein, from the fusion protein to the leukemia, a path had been traced for the rational design of this drug. From CGP-57148B to STI-571 and finally to imatinib mesylate and Gleevec, the world’s first drug targeted against a specific mutant protein that stopped cancer in its tracks was ready for wide release.”
It’s a model for a more targeted and intelligent way of treating cancer. The most sophisticated lessons of genetic research are applied to a kind of “personalized” drug development in which chemotherapeutic drugs attack very specific cancer cells. All this has happened with CML, though results with other forms of cancer have so far been much more limited.
Just as the story of the early research illuminates the byways of genetic research, the story of the development of the drug, Gleevec, involves collaborations between academic doctors and pharmaceutical companies, the fear of liability, even the politics of naming a new drug. Wapner uses her exhaustive research into this bench-to-bedside story to evoke controversies and complexities in science and medicine at every level.
This reporting takes in a huge swath of science and research, a landscape that changes dramatically over the course of her story. Wapner’s achievement is to help the reader understand why each development is huge in its time and place — starting with Hungerford peering through his camera at the chromosomes and following scientists through the laboratory stories, through drug development and animal testing, to the triumphant patient treatment when the drug becomes almost routine — a scientific miracle absorbed into the daily lives of a group of patients no longer united by a fatal diagnosis.
THE PHILADELPHIA CHROMOSOME
A Mutant Gene and the Quest
to Cure Cancer at the Genetic Level
By Jessica Wapner
The Experiment. 303 pp. $25.95