THE PHILADELPHIA CHROMOSOME: A Mutant Gene and the Quest to Cure Cancer at the Genetic Level

Aug 16, 2013

Jessica Wapner
The Experiment
ISBN 978-1615190676
303 pages
$25.95

Reviewed by Perri Klass

To tell the story in "The Philadelphia Chromosome," Jessica Wapner has to go back in scientific time and recreate 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 scientifically creative but technically 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 that brought that understanding along 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 as it has played out over the past three or four decades: The scientific steps along the way trace 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 particular Brian 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 from scratch 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. As these pieces were understood, 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 new and 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, in which 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, and it's 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 the context of its time and place - starting with Hungerford peering through his camera at the chromosomes and following scientists through the laboratory stories, through the 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.

Perri Klass is a professor of journalism and pediatrics and the director of the Arthur L. Carter Journalism Institute at New York University.

Copyright 2013 Washington Post Writers Group

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ISLAND OF VICE: Theodore Roosevelt's Doomed Quest to Clean up Sin-Loving New York

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Washington Post book reviewers

Apr 13, 2012 ARCHIVES  |  Entertainment  |  COLUMNS

Richard Zacks
Doubleday
ISBN 978-0385519724
431 pages
$27.95

Reviewed by Daniel Stashower

A clergyman, a detective and a society swell walk into a bar ...

It sounds like a vaudeville routine, but, as Richard Zacks reports in "Island of Vice," his jaunty and beautifully researched portrait of New York at the close of the 19th century, it was actually the opening salvo of "a holy war on vice and government collusion." The clergyman, Rev. Charles Parkhurst of the Madison Square Presbyterian Church, had delivered a blistering sermon a few days earlier - on Valentine's Day of 1892 - in which he called out the corrupt powerbrokers of the city's Tammany Hall political machine. According to Parkhurst, the mayor and his subordinates were a "lying, perjured, rum-soaked and libidinous lot" growing fat on the city's houses of sin through an entrenched system of bribes and rake-offs. Something had to be done.

When city officials fought back with libel charges, Parkhurst launched an unlikely fact-finding mission, hiring a private detective to conduct him and a devout blue-blood parishioner on a tour of New York's seamy side. "I never dreamed that any force of circumstances would ever draw me into contacts so coarse, so bestial, so consummately filthy," Parkhurst declared. At one stop, the reverend averted his eyes from a display of nude leapfrog; at another, he fended off a 19-year-old girl's blunt proposition. History has drawn a discreet veil over the carryings-on at the "French Circus" on West 4th Street, but certain statutes invoked at the time made reference to birds, animals and corpses.

In the end, Parkhurst presented the city's district attorney with a list of 284 gambling joints, brothels and after-hours saloons. "Now," he demanded, "what are you going to do with them?" The challenge led, in time, to a clean-sweep election that brought in a reform-minded mayor, as well as a intrepid new police commissioner by the name of Theodore Roosevelt.

Roosevelt, writes Zacks, "was then a work-in-progress, years removed from San Juan Hill and the White House." At age 36, Roosevelt freely admitted that he "knew nothing of police management," but he compensated with a winning optimism and boundless energy that initially endeared him to the city's population. With his friend Jacob Riis, the pioneering photojournalist, Roosevelt undertook a series of "midnight rambles," rattling the cages of patrol officers found sleeping on the job or otherwise derelict in their duties.

Roosevelt's efforts went off the rails soon enough when he chose to enforce the city's long-neglected Sabbath laws, which required saloons to close on Sundays. The measure posed no hardship to Roosevelt himself, who seldom drank, but it did not sit well with the populace, many of whom looked forward to knocking back a beer or two after a six-day work week. Saloonkeepers scrambled to find loopholes, and soon discovered that any establishment selling food as well as drink might call itself a "hotel," thereby circumventing the ban. It was not necessary, however, that the food be eaten, and more than one newly minted hotel provided an "an old dessicated ruin" of bread and cheese that could pass untouched from one customer to another to satisfy the requirement. Soon the policy became the subject of jokes: During a pause in service at a particular watering hole, disgruntled customers were told, "Some idiot has eaten the sandwich."

Zacks, whose earlier books include "The Pirate Hunter" and "History Laid Bare," seems to take a professional interest in scoundrels and sinners. He's right at home in fin-de-siecle New York, a time when the city had 30,000 prostitutes and 8,000 saloons available to a population of not quite 2 million people. He has pumped his book full of entertaining details about such things as a "dog's nose," an ungodly beverage made up of barrel dregs and leavings from the glasses of other drinkers, and a five-cent whiskey that tastes of "kerosene oil, soft soap, alcohol and the chemicals used in fire extingushers." Though Roosevelt is the marquee name in his drama, Zacks makes good use of a fascinating array of supporting players, including the corrupt precinct captain "Big Bill" Devery, "a true Hell's Kitchen New Yorker, mixing charm and menace," and the exotic, Algerian belly dancer Little Egypt, who was fond of appearing in what she called "zee altogether."

Against such "brilliant evil," as one newspaper phrased it, Roosevelt never stood a chance. Within two years, as the anti-vice crusade stalled out amid "constant bickerings between men who know better," he looked for greener pastures. By then the press had dismissed him as a "blue-blooded Knickerbocker" who would never amount to anything. The New York Mercury declared: "No Roosevelt was ever President; no Roosevelt ever led an army to victory - and none ever will." By April of 1897, he had decamped for Washington as assistant secretary of the navy.

"It is fascinating and somewhat uncanny," Zacks writes, "that despite one of the most concerted efforts in the history of New York City to crack down on whoring, gambling, and after-hours drinking that all three somehow thrived." Uncanny? Perhaps, but as O. Henry, another keen observer of the city's vices, once declared, "It couldn't have happened anywhere but in little old New York."

Daniel Stashower is the author of "The Beautiful Cigar Girl."

Copyright 2012 Washington Post Writers Group
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