The Philadelphia Chromosome: A Mutant Gene and the Quest to Cure Cancer at the Genetic Level

by Jessica Wapner, Robert A. Weinberg (Foreword)

One of Publishers Weekly’s Top Ten Spring 2013 Science Books

Philadelphia, 1959: A scientist scrutinizing a single human cell under a microscope detects a missing piece of DNA. That scientist, David Hungerford, had no way of knowing that he had stumbled upon the starting point of modern cancer research—the Philadelphia chromosome. This book charts not only that landmark discovery, but also—for the first time, all in one place—the full sequence of scientific and medical discoveries that brought about the first-ever successful treatment of a lethal cancer at the genetic level.

The significance of this mutant chromosome would take more than three decades to unravel; in 1990, it was recognized as the sole cause of a deadly blood cancer, chronic myeloid leukemia, or CML. This dramatic discovery launched a race involving doctors and researchers around the world, who recognized that in principle it might be possible to target CML at its genetic source.

Science journalist Jessica Wapner brings extensive original reporting to this book, including interviews with more than thirty-five people with a direct role in this story. Wapner reconstructs more than forty years of crucial breakthroughs, clearly explains the science behind them, and pays tribute to the dozens of researchers, doctors, and patients whose curiosity and determination restored the promise of a future to the more than 70,000 people worldwide who are diagnosed with CML each year. Chief among them is researcher and oncologist Dr. Brian Druker, whose dedication to his patients fueled his quest to do everything within his power to save them.

The Philadelphia Chromosome helps us to fully understand and appreciate just how pathbreaking, hard-won, and consequential are the achievements it recounts—and to understand the principles behind much of today’s most important cancer research, as doctors and scientists race to uncover and treat the genetic roots of a wide range of cancers.

Genres: Science, Nonfiction, Medicine, History, Biology, Medical, Genetics

320 pages, Hardcover

First published May 1, 2013

About the author

Jessica Wapner is a freelance writer focused on health, medicine and scientific research.

Reviews

[Pat Elliott · Rating 5 out of 5]

The story of "Philadelphia Chromosome" treatment is one you see listed on timelines that document the most significant milestones in the history of cancer treatment. It has been called "the closest thing we have to a cure for cancer." The book is the true account of a ground-breaking, life-saving treatment for cancer. How do I know? I'm one of the people alive today - and living well - with Chronic Myelogenous Leukemia, or CML, which previously was terminal for nearly every person who developed this blood cancer.

As a CML patient, and patient advocate, I'm intimately familiar with "The Philadelphia Chromosome" and yet learned many new details of this fascinating story from Jessica Wapner's book. As a science journalist, she has carefully and accurately captured the multiple and often seemingly disparate elements that came together over 40 years to develop the first successful treatment of cancer at the genetic level. At the same time she has explained terminology that would be unclear to those who are not familiar with hematology or oncology, making complex concepts more easily understood. She has humanized the players, including scientists and cancer patients, sharing the strong emotions that played a role in driving those who believed that cancer could be tackled at the genetic level.

While the book focuses on one cancer, it's full of lessons and key learnings for the future of cancer progress through the understanding of genetics and the personalization of treatment for individual patients. It's clear that several roadblocks were in the way and lengthened the time it took before lives were saved. In a time when scientific research is being cut back, this is an important book making it clear that we need to keep going forward and find ways to accelerate time frames, collaborate in the sciences, and give patients a voice, if we are serious about reducing the number of people who are dying from cancer.

[Mary · Rating 5 out of 5]

Renewed Appreciation

Reading the Philadelphia Chromosome transformed me into a mini scientist majoring in CML, Chronic Myelogenous Leukemia. I was diagnosed with CML in November of 2003, which required keeping up-to-date on news relating to CML. When I heard about the Philadelphia Chromosome by Jessica Wapner, I was anxious to add it to my shelf of resources.

Reading the book with pencil in hand to highlight new facts as well as valuable previous knowledge, I found myself marking information on every page.

When I was diagnosed my oncologist informed me that if there was ever a good time to get CML, it was now. At that precise moment, I had no idea what he was talking about. He may have elaborated, but in that moment of shock, I didn’t hear much. Wapner’s book has renewed my appreciation of that conversation every time I swallow my oral chemotherapy pill, Gleevec.

I have an entire file cabinet filled with lab results since 2003. My oncologist reviews the findings with me twice a year, but after reading the Philadelphia Chromosome, my understanding of the labs has improved. I have registered for a couple of CML conferences and am confident I will easily grasp new information presented after reading this book.

Years ago I started writing a book about living with CML. I found it too depressing to continue, however, not abandoning the therapeutic effect; I turned it into a blog, which I update once a month. marycrocco.wordpress.com Being helpful to a few readers who have stopped by makes it worthwhile.

Wapner shared a story of a patient who cherished her Gleevec and defended it with her life. I do the same thing, always insisting to sign for it and checking the delivery time is set for the morning. I don’t want my miracle pill losing its potency in the heat of a UPS truck.

Thank you, Jessica Wapner, for taking the time to write this incredible book, the Philadelphia Chromosome. I appreciate the effort required in your research to share with others who suffer with CML, or readers who have an interest in cancer treatments.

Bringing to life the names of medical doctors and institutions involved in the creation of Gleevec was important. I owe my life to Dr. Druker, and others, who dedicated a large portion of their lives creating a targeted medicine to fight chromosome abnormality in cancer cells.

[Rebecca · Rating 5 out of 5]

Place this book next to "The Emperor of all Maladies" on your shelf. It is an in depth history of the development of the science that led to the most effective treatment of CML. It is an interesting read--especially for those interested in drug development and the history of cancer.

[Cheenu · Rating 5 out of 5]

A very well written, engaging & hopeful book!

Tracks the successful development of an extremely effective drug for treatment of a rare cancer, chronic myeloid leukemia (CML).

The author does an amazing job of covering all the research, events and people involved in making this a reality, from the first academic researchers who studied the disease and discovered the genetic mutations in 1959.

The book also illuminates the collaboration between the academic institutions, pharmaceutical industry and the government regulatory agencies.

I appreciate that the author does take a pretty balanced and measured viewpoint on the pharmaceutical industry, reporting the facts as they are without judgement and when the facts are subjective, allows both sides to expresses themselves.

It is a little light on the science but I don't mind it as it makes it much more accessible.

Recommended! One of those encouraging, inspiring success stories of modern science.

[Christine · Rating 5 out of 5]

As a new-ish CML patient (diagnosed just over 3 months ago), this was such an amazing deep dive into what I consider to be a huge stroke of luck: I have largely been unaffected by my diagnosis, aside from some major improvements in my energy levels after my first few weeks on one of the second generation TKI’s, and that’s only true because of the medical research documented in this book and my good fortune of being born at a good point in history.

Even without that kind of personal connection, I think this would be a great read for folks who enjoy non-fiction and popular science. The peek at how vastly human understanding of the mechanics of cancer has changed in the past 50 years was mind-boggling. As the various puzzle pieces of the disparate research that was necessary to get to the successful treatment of CML unfolded over that multi-decade history, the suspense was palpable—even though I knew the ending!

Also, to comment on an old review here that I wanted to speak to. Saying this book turns into a commercial for pharma is just absurd. There’s plenty of criticism of Novartis in this book, as well as some straightforward explanation of the state of funding for the type of research that was crucial to creating this medication.

[Rand]

As a narrative, I found this to be at first too dry/boring and in the end, an annoying advertisement for the pharmaceutical industry. It began innocently enough, with a description of geneticists from the 1950s and then the overbearing story of someone who benefited from the fruits of those researchers.

Ultimately, this is a harrowing book of hope made hollow—much like any cancer-narrative that's allowed to metastasize in your conceptual apparatus.

I read most of this book, repeatedly, over the course of a year or two. The writing's not bad, per se, just dis-engaging. There's plenty of documentation for most of the author's claims, though do give the other reviews on this site a glance as the veracity/relevance of many of those claims remains questionable.

Maybe I'm just jaded because I believe that cancer could easily be cured/prevented by radically changing the typical western lifestyle/diet, and that information that could make cancer a non-threat is intentionally being suppressed by large corporations which control the world's leading governments. Yeah, yeah, yeah.

My review copy was furnished courtesy of the publisher in exchange for an honest review.

[First Second Books]

Never thought I'd be devouring a book on cancer research, but here I am… So far, a great read, sucking me in like The Immortal Life of Henrietta Lacks did…

[Paul · Rating 2 out of 5]

This book feels like an interesting narrative history of first the slow coalescence of the field of oncology and oncogenetics, and then eventually the development of Gleevac in particular. Unfortunately, though I don't know enough about the subject to really say how accurate it is, the few details I've spot checked are highly suspect, so I am not sure how accurate the story is.

The first "interesting fact" that I took note of was Wapner's story that Theophilus Painter originally mistakenly identified that there were 48 chromosomes in 24 pairs in 1921, and this error went uncorrected for 35 years, until Joe Hin Tjio, using more advanced techniques, identified the correct number as 46 chromosomes in 23 pairs. The book seems to suggest that this is because biologists were deferring to Painter, but looking into it a bit on my own, it seems like Painter had a seemingly reasonable methodology for determining chromosome number and several people using his methodology were able to duplicate his findings. This paper seems to suggest that some unique features of chromosome 1 make it look like 2 pairs of chromosomes under the type of staining Painter was using. While Wapner's verison of the events is represented in the secondary sources (e.g. here), it seems to me that both Wapner and the secondary source I found are interested in telling a specific (or at least a compelling) narrative, and so leave out the alternate and more mundane explanations.

I also got the impression that the book was suggesting that the nature of cancer was not understood until surprisingly late — 1959! This quote, in particular:

“Until we stumbled over this Philadelphia chromosome, there was really no evidence that cancer might be due to genetic change,” Nowell, now 79, said decades later. This photograph would become the lasting portrayal of a moment when everything changed for cancer and medicine as a whole. It was the as-yet unrecognized starting point for the modern era of targeting cancer at its root cause.

But this seems at odds with this quote from Wikipedia's article on the History of Cancer:

The genetic basis of cancer was recognised in 1902 by the German zoologist Theodor Boveri, professor of zoology at Munich and later in Würzburg. He discovered a method to generate cells with multiple copies of the centrosome, a structure he discovered and named. He postulated that chromosomes were distinct and transmitted different inheritance factors. He suggested that mutations of the chromosomes could generate a cell with unlimited growth potential which could be passed on to its descendants. He proposed the existence of cell cycle checkpoints, tumor suppressor genes and oncogenes. He speculated that cancers might be caused or promoted by radiation, physical or chemical injuries, or by pathogenic microorganisms.

The citation is to J Cell Sci (2008) 121 (Supplement_1): 1–84; DOI:10.1242/jcs.025742. This seems like a much more plausible timeline to me. I have to assume that Nowell is referring to something much more specific than "cancer is caused by genetic change", maybe "blood cancer" or "CML", but this is the second thing I fact-checked from the book, and both turned out to be very misleading, so that's not a great sign for the general accuracy of this book.

Additionally, up until the end of the book, it sounded like Gleevac was basically a cure for CML. She kept talking about the Philadelphia chromosome number of various patients going down to 0, which sounds like, you know, it isn't there. It isn't until the very end of the book that it becomes more clear that it's actually a chronic treatment. When I mentioned this to my doctor friend, he also seemed to suggest that people's CML tends to develop resistance to the drug and they eventually need to be switched to the next generation therapies, which, if it's present in the book at all seems to be downplayed.

The book also seems to make a big deal out of how Gleevac was going to be an orphan drug, and the pharmaceutical companies didn't want to run trials for it because they thought that they would never make their money back. This is a running narrative in the book (and probably was a running narrative at the time), but then when Gleevac comes out it's a blockbuster drug and makes billions of dollars. It is not at all clear to me what the disconnect was. Did the pharmaceutical companies underestimate the number of people with CML? Did they underestimate the amount of people who would want it? Did they assume there would be competition? None of this seems addressed, she just jumps directly into some talking points about how they seem to have made too much money off of it. I don't even think too much of this was inaccurate, I just don't know why it's not glaringly obvious that there's a mystery to be explained here. Additionally, this is really just my own hobby horse, but I would like to point out that even if there is just the perception that a drug won't do well on a market, pharmaceutical companies won't do the trials required by the FDA, and thus even people who would be happy to try the drugs without a trial are prevented from doing so. Would be nice if more people realized how many people our current FDA regime kills this way.

Overall it's a compelling narrative structure, and some of the biographical details of the various people involved seem interesting, but at the end of the day I find it hard to trust anything in this book because of the narrative bias and the things I found that don't seem to bear up to scrutiny.

2 of 5 stars

[Darryl · Rating 5 out of 5]

In 1959 two Philadelphia researchers, David Hungerford, a scientist at the Fox Chase Cancer Center, and Peter Newell, a physician studying cancer at the University of Pennsylvania School of Medicine, made a momentous discovery that revolutionized the understanding of cancer. Hungerford, who specialized in studying and photographing chromosomes from a variety of species, looked at a slide of the cancerous cells from a patient with chronic myelogenous leukemia (CML), using a technique of halting chromosomes during division that was designed by Newell. To his great surprise, Hungerford noticed that one of the chromosomes was significantly shorter than it should have been. He took a photograph of the shortened chromosome and showed it to Newell, who subsequently prepared slides of cancerous cells from several other people with CML. Each of these patients had the same abnormal chromosome. The two published their findings in a three paragraph article in Science the following year. The study was largely ignored, as the study of genetics was in its infancy, and essentially no one suspected that cancer could be caused by chromosomal abnormalities.

Over a decade later Janet Rowley, a geneticist at the University of Chicago, studied these same cells from CML patients, using staining and visualization techniques that weren't available to Hungerford and Newell. She found the same shortened chromosome, which was by then determined to be chromosome 22, but she also found that chromosome 9 was also abnormal, being longer than it should have been. Through meticulous study of these chromosomes she correctly determined that a portion of chromosome 22 had migrated to chromosome 9, while a similar portion of chromosome 9 appeared on chromosome 22, in a process that is known as chromosomal translocation:



This translocation led to the creation of a fusion gene, made up of a portion of the abl gene of chromosome 9 and the bcr gene of chromosome 22. The bcr-abl gene, known as an oncogene, led to the production of a protein that allowed the affected cell to rapidly multiply without the normal controls exhibited by other cell types. Similar to the famous Trouble with Tribbles episode of Star Trek, the cancerous cells, which are derived from immature white blood cells, overtake the bone marrow, leading to decreased production of the normal bone marrow cells: red blood cells, normal white blood cells and platelets.



Initially this causes anemia, leukopenia and thrombocytopenia, or decreased red blood cells, white blood cells and platelets in the circulatory system, respectively. As the cancerous cells continue to multiply they escape from the bone marrow and make their way into the bloodstream in large numbers, which causes profound leukocytosis, or an excessive number of white blood cells in the circulatory system. Leukemia is often diagnosed at this stage, when the blood is filled with abnormally large white blood cells.


Photo Credits: Eric V. Grave / Photo Researchers, Inc., ISM/Phototake

Without any treatment to block the uncontrolled multiplication of these leukemic cells they migrate to other organs, which leads to organ dysfunction and ultimately death.

In The Philadelphia Chromosome, Jessica Wapner brilliantly describes the painstaking research by scientists and clinicians to elucidate the mechanisms on a genetic and molecular level that lead to cancer, including the study of cancer causing viruses such as Rous sarcoma virus and Moloney virus, and the discovery of tyrosine kinase and other protein kinases, which are essential to normal function and growth in healthy cells but can cause unregulated division in cancerous cells. The bcr-abl in CML cells was discovered to code for an abnormal tyrosine kinase, and a collaboration between academia and the pharmaceutical industry led to the eventual development of the first tyrosine kinase inhibitor, imatinib mesylate, which is also known as Gleevec in the US and Glivec in most of the rest of the world. The use of this and subsequent tyrosine kinase inhibitors has allowed people with CML to live near normal lives by taking one pill a day, with minimal side effects; until the 1980s CML was a universally fatal disease. Other kinase inhibitors and similar compounds are under development, which have not yet been as successful in treating other malignancies but hold promise that cancer can be successfully controlled, if not cured, in our lifetimes.

The Philadelphia Chromosome is a carefully researched and very well written book, given the complexity of the techniques used in molecular biology and genetics, which also reads like a suspense novel as Wapner describes the hurdles that the discoverers of the first tyrosine kinase inhibitor faced in getting Novartis, its manufacturer, to approve the drug for clinical trials and make it available to the general public. It is a very important and timely book, which I would recommend to all readers, although it may prove to be a bit of a challenge for those readers without a basic science background. It is nearly as good as Siddharta Mukherjee's Pulitzer Prize winning book The Emperor of All Maladies The Biography of Cancer, and it would be a perfect next step for those wishing to learn more detail about cancer research after reading that book.

[Ilayda · Rating 4 out of 5]

4.5🌟/5!!! Literally finished this book in a day, I can’t believe it was so captivating?! I’m shocked that i’m giving a non-fiction a 4.5/5 stars and that it was so good I read it in one go!!! The only reason I didn’t give it 5 stars is the book got a bit dry towards Part 3 where there was a lot of discussion on FDA approval of the drug created, and sm about the cost. So thankful for the NHS every day, it was crazy seeing this from the American healthcare POV since the drug was created there, and the mind-boggling cost of the drug— annual cost of $33,000 per patient …… WHAT😭 And it’s completely free under the NHS for patients with CML/ any other Ph+ cancer. Anyway lol, I only read it for a personal statement & it’s literally so random to read otherwise so I understand if you might not want to pick it up, but if you’re interested in this stuff i’d defo recommend/ watch a documentary on the Philadelphia chromosome’s discovery in general, it’s suppppeeerr duper interesting!!!

[Aryana R · Rating 4 out of 5]

My chest ached reading the last words of this book, “enjoy life”. For a book with such a slow start it had me invested by part 3/4. The amount of politics in drug development was shocking and delicious. While I hurt for the real people who suffered from the delays, I also ate up the rollercoaster like hot gossip. I read this book because I loved Emperor of all Maladies. It didn’t really live up to that book, but that’s fine because this book felt uniquely journalistic - putting a magnifying glass on ego, greed, he said/she said dynamics and the fallibilities of each person involved. If you can get through the first 1/4 (think heavy background, lots of names with no personality to help remember them) definitely recommend.

[Kathy · Rating 5 out of 5]

Like a page-turning murder mystery where cancer is the killer and scientists are the heroes, Wapner clearly explains the round-about and sometimes random series of discoveries that lead to a near cure for chronic myeloid leukemia.

[April · Rating 4 out of 5]

I did really enjoy this book even though the first half or so is very science-heavy in areas that I have little knowledge of. The last half is much easier to read and I did find the story of cancer drug research to be pretty interesting.

[Murilo Forte · Rating 4 out of 5]

“The way the Philadelphia chromosome led to CML was a story that unfolded like a hundred painters applying brushes to a canvas at some time or another over twenty-five years, driven only by curiosity and, sometimes, a vague hope that their work might eventually be relevant to human cancer.”

"Give the drug a chance."

"This drug has been engineered in the laboratory to target a single, cancer-causing protein, and like a light switch, turn off its signal to produce leukemia cells." — Tommy Thompson

"Every scientific breakthrough, no matter how technical it seems, holds the power to transform lives, saving them and giving them new possibilities."

[Sherif Gerges · Rating 5 out of 5]

This is one of the most amazing popular science books I’ve read. Wapner achieves a great balance; scientifically rigorous yet deeply compelling. She dives deep into the complexities of cancer and the hidden machinery of drug development, yet presents it with such clarity and narrative force that it never loses momentum. Intellectually satisfying for PhDs, yet engaging for any curious reader. An awesome book.

[Briana V · Rating 5 out of 5]

4.5 Stars.

[Dominic · Rating 5 out of 5]

Fantastic chronicling of CML’s early research days and the long process of the first example of rational drug design. Also a neat look at the behind-the-scenes of academia-industry collaborations

[Marina Blackwell · Rating 4 out of 5]

Very interesting but also deterred me from ever trying to create a medical product/drug and get it FDA approved it seems like a total nightmare.

[Sylph · Rating 5 out of 5]

This was a great piece of scientific journalism offering a well researched look into the history behind the development of the drugs that can be used to treat and cure CML.

[Donna · Rating 2 out of 5]

Am I being harsh with a two star rating? Probably, yeah, but oh boy was this a long, hard slog of a read.

This is a book about the development of the first drug that targeted a genetic mutation directly to treat a cancer caused by that genetic mutation. It looks at the history of scientific exploration and discovery that led to the mutation, the titular Philadelphia chromosome, and how it resulted in new ideas for how cancer could be treated, opening new avenues of research, and how a drug (now known as Gleevec) targeting the misshapen protein that results from the Philadelphia chromosome was conceived of, developed, and produced. It focuses on the scientists, clinicians, patients, and businesspeople whose hard work, dedication, and bravery led to Gleevec. It looks at what happened after, the second- and third-generation treatments, the high hopes and crushing disappointments as subsequent treatments failed to live up to the promise of Gleevec, the future of cancer treatment today (well, as of 2013-2014, when the book was published/the softcover edition came out).

It is also TERRIBLY written.

These days, I try to limit my reviews to my reaction and experience reading a book. Just because something isn't for me or didn't meet me in the right mood doesn't mean that the author deserves to be attacked (even if I'm sure they'll never read this). And I'm sure Wapner cared a lot about this project and put a lot of effort into research and writing.

Which is why I think her publisher FAILED her, UTTERLY.

I don't know much about the ins and outs of the book industry. So I don't know at what stage in the process an editor is hired to proofread, fact check, and perhaps provide gentle suggestions for story structure.

I would like to talk about scientific research and how it's funded and what the incentives are and how there's not enough room for young people or creativity these days because everyone wants to maximize profits and stick with established things and Gleevec sounds like Emma's first word on Friends, but I can't. Because I have over 100 highlights noted in my Kindle edition, and about 90% of them are rants about editing.

Witness:

If the cell is like a house, then identifying src’s product was like pointing to a single part of the house and declaring it important.

If cancer is like a gun, then the kinase is like the finger behind the trigger.

In the hunt for cancer’s underlying mechanism, finding tyrosine was like a tracker finding an animal’s footprint or a broken branch.

Like pieces on a chessboard assembling for checkmate, discoveries and researchers were slowly coming together.

Like a balloon, and...something bad happens!


Like an impressionable child, these embryonic cells proved susceptible to the virus outside of the protective shield of the womb.

like a metal detector scanning for gold lost underneath the sand.

It was like moving from the broad strokes of Matisse to the pointillism of Seurat.

At this point, I was starting to lose it.

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.

like a relay race in which the gene shoots the gun and the kinase is the first runner.

It was like finding the leaky faucet responsible for a persistent dripping noise.

like a mountain climber finding a jutting rock for his next step.

THIS BOOK IS NOT THAT LONG. HOW IS THIS STILL GOING?

Like a gloved hand fitting perfectly over a mouth to block the next breath, the drug would stop the runaway kinase in its tracks, thereby halting cancer progression.

The amount of phosphotyrosine revealed by the antibody reflected the amount of active kinase. It was like counting the number of sand castles to estimate how many children had been at the beach.

The flag methyl group forced the compound into one immovable arrangement, like a host finalizing the seating for a dinner party.

It was like stopping a car by removing the gas pedal instead of the motor.

I swear to fucking Hades, if I read one more needless, incomprehensible simile, I will...finish reading the entire book because I don't value my personal time at all, I guess.

Then there's the stuff that's just...wrong? Or weirdly written and underexplained?

For example, in the prelude:

The first few days of treatment [Gleevec] were pure hell. Eichner vomited several times a day, often through the night, and the nausea kept him from sleeping.

But in chapter 25:

The STI-571 [Gleevec] experience wasn’t normal. This wasn’t how cancer treatment worked. Patients were supposed to be doubled over in agony, vomiting into waste bins at the side of their bed

So...much like Eichner was in the very beginning? I get what she's trying to say here, that the side effects were relatively bearable and not long-lasting, especially when compared to cancer treatments like chemo or Interferon. But then say that. Don't LITERALLY USE VOMITING AS AN ILLUSTRATION OF A SIDE EFFECT WHEN INTRODUCING YOUR READER TO GLEEVEC AND THEN SAY THAT GLEEVEC DOESN'T HAVE SIDE EFFECTS LIKE VOMITING.

corticosteroids (synthetically manufactured versions of hormones produced by our adrenal glands)

Um? Corticosteroids are hormones, only synthetic corticosteroids are synthetic.

further confirming the central role of the Abl

Further confirming? Okay, 1, something either is or is not confirmed, it doesn't need FURTHER, and 2, science! We support hypotheses, we don't confirm them!

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.

...I mean, had he? They needed to contract someone else to make the compound because his attempts were all failures!

The understanding that Matter brought to Zimmermann, isolated in the lab as he was, were enough to sustain his determination to do what Matter was asking them to do.

I just...what does that even mean?

Also, while I'm complaining, why were the image numbers not in the order the images appeared? Is this just a Kindle problem? Why wouldn't they be numbered in order of appearance?

There is a good book in here, there is. But it reminds me of what my writing looked like in J-school when I was in the middle of an assignment. I would group info, quotes from sources, and phrases together in sections, and cut and paste these sections when trying to decide how to structure the article. Before the last few re-reads, there would be a bunch of sentences all kind of saying the same thing ending up together, and I would have to, you know, EDIT. Sometimes that meant removing a quote from a source I really liked, or a sentence of my own I really liked, but I had to pick one.

Like:

The persistent pleading from clinicians on the outside gave Matter the confidence to keep fighting. The letter from Druker and all the other voices in support of the drug gave Matter the boost he needed. [...] “Without [everyone] covering my back, I don’t know whether I would have had the stamina to see this through,” Matter said.

or

As the [clinical] trial finally got under way, Druker remembered Bud Romine’s letter from two years earlier [...] When it was time to start enrolling patients, Druker remembered the bold request.

PICK. ONE.

Or take the following four sentences, which I promise you, all occurred on the SAME FREAKING PAGE:

Every known kinase placed phosphates onto either serine or threonine.

every other kinase known at that time brought phosphate only to either serine or threonine.

The other 900-plus proteins use serine, threonine, or a combination of both.

Of the several kinases known at that point, all stuck their phosphates onto serine or threonine.

FUCKING WHY?!

When people take interferon, they often develop a fever, chills, and a paralyzing fatigue, like having a flu that lasts for months or even years at a time. The drug can also cause severe depression.

they would remember the decimation wrought by the drug: the tiredness, the persistent flu-like symptoms, the depression.


ARGH


For the first time, he allowed himself to believe in what was happening. As he watched the tears roll down their cheeks, Druker shed his own as he finally allowed himself to believe what was happening.

That's just -- that's just two sentences right next to each other. Not even a paragraph between them.

Every large company has a kinase inhibitor pipeline: Novartis, AstraZeneca, Bayer, Johnson & Johnson, Merck, Pfizer, Eli Lilly, GlaxoSmithKline, and AstraZeneca [emphasis mine]

NO. STOP.

Why am I harping on this? Because I actually cannot believe how bad it is. This was not a self-published book. This is not something tiny that slipped through. This is EVERYWHERE. There is no excuse for it. How did this happen?

The Philadelphia Chromosome was called one of the 10 best nonfiction books of the year by the Wall Street Journal. It has three pages of accolades at the beginning. It's rated over four stars on Goodreads. How? HOOWWWW?! Do other people just not care about this stuff? Maybe it's like how Netflix shows these days all have their characters explain their exact feelings and motivations so people can half-watch while cooking or doing their laundry. Are y'all just skimming? WHAT IS GOING ON? PLEASE JUST HIRE ME TO EDIT YOUR BOOKS, IT IS MY DEFAULT SETTING, I CANNOT TURN IT OFF.

[Marci · Rating 5 out of 5]

If you appreciate good science writing and an interest in translational research, I highly recommend this book.

[Kerry · Rating 5 out of 5]

Fascinating!! This is the amazing story of the development of oral cancer drug Gleevec (imatinib), the so called "magic bullet" in treating CML (chronic myeloid leukemia), a truly miracle story in the treatment of CML and subsequently a few other rare cancers including gastrointestinal stromal tumor (GIST). I have particular interest in the story as I am a beneficiary of the benefits of Gleevec. I was diagnosed with GIST and have been taking Gleevec for 7 months. Before the development of Gleevec there was no successful treatment for advanced or metastatic GIST. It is an oral cancer drug, a pill which can be taken at home and has very minor, manageable side effects. I do not have a scientific background, although I have suddenly found myself taking a crash course in GIST, tyrosine kinase inhibitors, and Gleevec, yet I found the book readable for a layperson.

I expected most of the reviews to be by people like myself that have a particular interest in Gleevec or CML however there are excellent reviews by other readers as well. It is an amazing story and offers much insight into cancer research and the development of drugs as well as the downside in the delays and politics of such and the prohibitive costs.

While the book is about the development of Gleevec and the treatment of CML there are a few references in the latter part of the book regarding the treatment of GIST. Although I was prescribed to take the Gleevec daily, I learned from the book how the drug works and the importance of taking the pill without fail each day and close to the same time each day. My doctors had not really explained this or the importance or why of this.

I was fascinated with the book and the story of the many people involved over 40 years. I am so grateful for this drug which is saving so many lives, which may be saving my own life, and which is offering hope to many people who would have had no treatment or no hope 15-16 years ago.

I hope that the breakthrough with this drug and this disease will continue to lead in the progress of treatment for other cancers.

[Katie · Rating 5 out of 5]

Summary: This was a fascinating, easy-to-follow story of an awesome of scientific success.

For decades, the only way to treat cancer was with un-targeted therapies that had terrible side-effects. This is the story of the first cancer treatment that targeted the specific, genetic mechanism that caused a specific cancer - the Philadelphia chromosomal mutation that causes chronic myeloid leukemia. Like many scientific discoveries, the identification of this cancer treatment is a complex and intriguing story involving many lines of research. Despite the near-miraculous success of the resulting treatment, the story of the drug development that followed is equally convoluted.

As a scientist, I'm a huge fan of books that realistically portray scientific research and I thought this book did a particularly good job of showing what an incremental, collaborative venture science is. Throughout, I was impressed by how the author managed all of the different stories about all of the scientists involved. Despite the many storylines, I felt as though I got to know about many of the key players personally. Brief recaps at the beginning and endings of many chapters made this complex story easier to follow.

The science was also explained clearly. I thought the author made a very smart decision to include an appendix defining many basic terms. This allowed her to spend less time on explanations in the text. She did still have some great explanations though, with very clever analogies that achieved clarity without dumbing things down or losing any of the nuance. It was everything I look for in science nonfiction.

Do you have any favorite science nonfiction books you'd recommend?

 
This review was originally posted on Doing Dewey

[Aparna · Rating 5 out of 5]

The author has a versatile experience and has written the book with such thorough knowledge of the challenges and thrills of scientific research as well as the pros, cons and internal politics of the pharma industry. Learnt quite a bit of regulatory strategic terms of drug development. The author elegantly explains how long, frustrating yet rewarding a scientific journey could be and how heavy of a history would be behind a cure for cancer... The significance of collaboration between academia and industry has been emphasized. The importance of funding basic research as well as translational/clinical research is well- emphasized.

[JoAnn · Rating 5 out of 5]

I loved this book... absolutely loved it!

In my previous life, I was a clinical pharmacist at a teaching hospital. We were involved in many drug trials, particularly for cancer and AIDS. This book brought back all the excitement, exhilaration, tedium, and frustration associated with those trials.

The Philadelphia Chromosome chronicles the research, discoveries, development, and clinical trials involved in bringing the revolutionary drug Gleevec to market. Gleevec represented a major breakthrough in the treatment of CML (chronic myelogenous leukemia) and basically transformed a death sentence into a more manageable disease.

Initially the book made my brain hurt. It brought back memories of organic chemistry, microbiology, biochemistry, and genetics. It jogged my mind to recall specific terms and principles I hadn't thought about in decades. But as soon as Wapner got to the medical part - hospital/patients/drug trials - I was in my element.

I am SO glad I listened to this book. The hard science at the beginning may have been too much for me in print, but once we got to the drug itself, the audio literally kept me up at night. {Go ahead, call me a nerd!} I can't even believe I'm saying a book like this was riveting, but it really was... especially in the second half as researchers/physicians were navigating the world of drug company politics and FDA protocols.

The Philadelphia Chromosome will not be everyone's cup of tea, but I couldn't get enough.

[Rob Slaven · Rating 5 out of 5]

As is usually the case, I received this book free. Unfortunately, I'm unable to determine the source of that freeness but suffice to say it came in the mail specifically for my review.

Typically, I review books based on qualitative properties, but in this case it's not really necessary. The book is sharp, thorough, professional and detailed. There's no real need to go into specifics about that. The more important thing to say may be to discuss exactly what this book is.

Topically, the book is a fairly even split between science and history. The author goes into a surprisingly great depth about the science involved and readers are encouraged to take notes along the way to make sure they keep up properly. This is no pop-science read; it expects readers to be as sharp and keep up. New terms are defined when used but typically just once and there's no fear in the writer about delving into technicalities.

On the historical side, the dozens of professionals involved are described in terms of their specific contributions and once those are complete, they step aside and are never heard from again. While there is a strong biographical component, it's really a biography of a disease rather than any of the people involved.

In summary, a painstakingly thorough treatment of an important topic but not for the faint of heart with reams of detailed technical information

[Bassim Zantout · Rating 5 out of 5]

The first question that occurred to me when I came across Jessica Wapner’s book “The Philadelphia Chromosome” was: do we really need a whole book to tell us the story of this abnormal chromosome? My answer was of course we do and for two important reasons that are closely related to the history of the oncogene. First, the story of the Philadelphia chromosome represents, in a very substantial way, the history of all the oncogenes that researchers began to uncover in the human genome, starting in the 1980s. It is a very long and complex history. It began when the American cancer Researcher Peyton Rous discovered a virus that caused sarcoma-a malignancy of the body’s connective tissues-in chicken in 1911. Later the virus was dubbed Rous Sarcoma Virus (RSV) in deference to its discoverer. It is a complex history as it involves contributions from genetics, biochemistry, immunology and molecular and cell biology. These various contributions over the span of the 20th century will ultimately culminate in establishing the genetic basis of cancer, including human cancer.
Second, the drug designed to treat chronic myeloid leukemia (CML), the white blood cell malignancy that is caused by an abnormal gene carried by the Philadelphia chromosome, represents the first and most effective exemplification of what is known as “rational drug design”. In very simple terms, rational drug design involves the identification of a target that is shown to induce the malignant process and the design of a drug that blocks this target to induce remission.
In the first part of her book, Wapner presents that history in a very accessible manner that can be easily followed by the interested lay reader. In that part of the book, the author also puts forward the proposition that two strands of research, the discovery of the origin of the RSV oncogene and the identification of the protein product of that oncogene, though unrelated to the discovery of the Philadelphia chromosome, ultimately converged to provide an understanding of the nature, function and role of this abnormal chromosome in the development of CML. To some extent this is a valid and plausible proposition, but it gives the reader the impression that the Philadelphia chromosome, which was discovered by Peter Nowell and David Hungerford in 1960, has a unique story.
In fact, the first strand of research, the discovery of the RSV oncogene which was later known as the src oncogene, provided unequivocal evidence that this cancer driver is not viral but cellular in origin. In other words, the virus captures this gene from the host cell. This discovery, made in 1976 by cancer researchers Michael Bishop and Harold Varmus who were awarded the Nobel prize for this research, radically changed the cancer research landscape and how researchers conceptualized the nature of cancer. Cancer became a genetic disease. From that point on researchers turned their attention to human cancers and began tilling the human genome in search for those oncogenes. The new path in cancer research lead to the discovery not only of the Bcr/Abl oncogene, the oncogene carried by the Philadelphia chromosome, but many of the other oncogenes that investigation has shown play a role in human cancers. Today these oncogenes count in the hundreds.
The remaining chapters of Wapner’s book basically tell the story of the discovery and development of the drug, later to carry the brand name Gleevec, for the treatment of CML. This is where, in my view, the uniqueness of the story of the Philadelphia chromosome resides and where the second strand of research, the discovery of the abnormal protein product of the src oncogene comes into play. Different research trajectories, from the mid-seventies and early eighties, provided evidence that the protein encoded by the src oncogene, and by extension the human counterpart, was a protein kinase, which is an enzyme involved in protein phosphorylation. More research uncovered the fact that this kinase phosphorylates an amino acid called tyrosine, hence the name tyrosine kinase. The Bcr/Abl of CML, it turned out, was a tyrosine kinase as well. In fact, researchers have shown that protein phosphorylation is
a universal mechanism in many cellular processes, such as cell growth, proliferation, differentiation, motility and survival. It is when this mechanism becomes deregulated, under the influence of a mutated gene, as in the case of the fusion gene Bcr/Abl, that malignant transformation ensues.
Study of cells of patients with CML has indicated that the abnormal Philadelphia chromosome is a consistent finding and is present in 95% of cases. That fact made the Bcr/Abl a causal determinant of this malignant disease. In other words, the Bcr/Abl oncogene is the necessary and sufficient condition for the development of CML. In many other cancers, malignancy is a multistep process that involves several genetic mutations as well as epigenetic factors. But not in CML. Stated differently, CML is dependent for its development on this oncogene. In oncology lingo, this is known as oncogene addiction, which can be taken advantage of to develop new therapies for cancers that are characterized as such.
In 1984, aware of the strong link between the Bcr/Abl and CML, a group of researchers at the Swiss pharmaceutical company Ciba-Geigy-before its merger with Sandoz, which is another Swiss company, to form Novartis-came up the idea that by blocking this abnormal gene, or its product the tyrosine kinase, the malignant process in those patients can be brought to a screeching halt. They discovered a compound that does just that. Imatinib, the scientific name of Gleevec, has been shown to be very effective as a tyrosine kinase inhibitor. Wapner writes about how in phase I clinical trials, which were supposed to be aimed at testing the safety of a newly developed drug, patients were showing an incredible response. The treatment of chronic myelogenous leukemia provided the earliest and best example of rational drug design or what became known as targeted therapy.
In 1960 Peter Nowell and David Hungerford at the University of Pennsylvania, School of Medicine in Philadelphia published a very brief note in Science magazine in which they talked about their observation of a “minute chromosome” that they found in the malignant white blood cells of patients with CML. They ended this brief note with a very prescient statement: “…the minute chromosome is not part of the normal chromosome constitution of such individuals [CML patients]. The findings suggest a causal relationship between the chromosome abnormality… and chronic granulocytic leukemia.” They were right!

[Cooper Wang · Rating 5 out of 5]

Cancer has troubled humans for a long time with its painful effects and difficulties of treating, and Leukemia is one of them. The book Philadelphia Chromosome focuses on the development of the drug against Leukemia, with the different chapters covering the history form the discovery of the DNA mutation that causes Leukemia to the clinical trials and the eventual approval of the medicine. The author’s purpose is mainly to educate the readers on the different details and events that contributed to the eventual success of the medicine, which makes it extremely interesting for the readers who are interested in the process behind the development of different medicines.

The book starts off with the patient Gary Eichner’s diagnosis of Leukemia and his recovery after taking medicines, which illustrates how easy it is to treat early-stage Leukemia in the current world. However, the book then proceeds to bring the readers back to the start of the process, with scientists trying to discover what exactly is causing the cancer in human bodies. The book follows the work of several researchers such as David Hungerford, Ray Erikson, and Herb Abelson, who all contributed independently to the eventual discovery of the key mutation that causes the cancer, which is a mutation that switches pieces of genes on the 9th chromosome to the 22nd chromosome. As a result, the tyrosine kinase, which is an important enzyme that is responsible for activation of different cells, malfunctions and creates an abundance of white blood cells, leading to cancer.

Now with the scientists understanding the underlying causes of the cancer, the book follows them closely with the development of the drug that would potentially cure cancer. One of the many plans is the rational drug design, which is theory that a certain chemical could block the tyrosine but not the other kinases and therefore stop the excessive production of white blood cells. While many people disagreed with the plan, stating that such chemicals would block the other kinases along the way and cause serious conditions, the proponents eventually started the project and started to synthesize the chemicals.

After some trials and errors, the researchers eventually ended up with a chemical that worked on the kinases and successfully inhibited it. However, the road for it to become a drug is extremely arduous. First, the chemical encountered difficulties during the trials on animals, and many of them faced conditions such as liver damage after taking the drug. While the condition might be caused by other preexisting factors in the animals, the results casted further doubts on the effectiveness on the drug.

However, Brian Druker, the lead researcher in the development of the drug, persisted to push the medicine into phase 1 clinical trials. While the drugs did not show their effects on the patients at first, as the testing protocol requires the drug doses to be small at first, the drugs started to demonstrate effects when the dose is raised to 200 milligrams, and the effects continue to improve with the increase in dosage. Thus, after seeing the results of Phase 1 trials, the company decided to move on with phase 2 trials, which included more participants. Moreover, Dr. Druker decided to change the protocols of enrollment, as while the usual protocol is to experiment with the patients at early stages of the disease, the phase 2 trials focused on the patients who are in the accelerated stage or late stage of the disease. The experiment also experienced large successes. Thus, the company started to prepare for phase 3 trials, which would include even more participants, along with the process of seeking FDA approval and making the drug available on the market. While the company was initially short on drugs and could not enroll many of the patients into the trial of the program, the production soon caught up and made the drug available to most of the patients. At last, after collecting enough data, and sending them to the FDA for approval, the drug was approved and named Gleevec.

However, other than the history of the development of the drug, the book also covered some of the problems that existed in the medical world. For example, the orphan drugs, which are drugs that are developed for a disease that only affects a small amount of the people, would be granted seven years of market monopoly even after the patent has expired to incentivize the companies to develop them. As a result, many of the drugs that target a small amount of the population are often extremely expensive due to this. Another example is that due to the lack of medicine production, many patients had to wait to enter the phase 2 trials for the drug. Even though Dr. Druker did his best to prioritize the people with the most urgent situation, many patients still died from not entering the trials. Thus, the book also demonstrated problems in the medical area that could be improved.

Jessica Wapner is an experienced journalists who specializes in writing about science. In the case of Philadelphia Chromosome, the book is very engaging to read, especially for people who are not familiar with the area of oncology or people who have interest in the area of medicine development. The book is written is terms that are relatively easy for people to understand, and the overall storyline is very engaging for the average reader. For example, the first few chapters might seem random in its organization, as the different chapters talk about the stories of different people in different time periods. However, the book manages to eventually describe how these different contributions eventually came together to create the necessary condition for the discovery of the internal logic of the disease and its cure. As a result, the book is great in terms of presenting an accurate picture of the history to the readers. However, it also has certain weak points, as while the terms are relatively easy to understand, it still requires certain amount of basic biology knowledge for a person to understand it fully. In conclusion, the book is very useful for understanding the history behind Leukemia and Gleevec, and I would recommend it to anyone who is interested in oncology or the medical industry.

[Larry · Rating 4 out of 5]

This is a very good companion piece to Siddhartha Mukherjee's, The Emperor of All Maladies: A Biography of Cancer. It could easily serve as a welcome and more detailed look at the last portions of Mukherjee's book. While there is plenty of depth to both books, not all participants in the battle against cancer over the many years come out looking very saintly. The Emperor of All Maladies has a rather jaundiced view of a number of cancer physicians, and The Philadelphia Chromosome author points out many of the shortcomings of drug companies. Nevertheless, this author does make a solid effort to share the drug companies' public relations position papers with a straight face. Having read Mukherjee's book before this one, it is quite difficult to say how much I would have appreciated this one without the knowledge of the first one. My gut tells me I would have enjoyed the book anyway, but that I have a more extensive and accurate assessment of where we are with our battle with cancer because of reading both. Frankly, I can't imagine facing a possible cancer diagnosis without the knowledge I now have.

[Maria · Rating 5 out of 5]

I got this book for free through Goodreads First Reads.

I'm really glad that I got this book. It was very informative and educational. At first I thought that I wouldn't understand much of it and would need to do additional research about the terms and concepts in the book as it was about cancer research and how that has evolved over time, but I shouldn't have been. Not only was the book very well-written and easy to read, the author, Jessica Wapner, defined every term and concept that she used in the book in words that anyone should be able to understand. If you have taken a high school biology class, you will understand this book. (The only reason you need that introduction to biology is so that you know what a cell is and what things like test tubes are, though you shouldn't even need schooling for that.) I would definitely recommend this book to anyone that has any interest in cancer and wants to read a book that will guide them through the journey that the medical field has taken. 5 stars from me!