Book Review: the Philadelphia Chromosome by Jessica Wapner

3 stars: interesting topic and history but science too dumbed-down

Disclaimer: Unfortunately I'm just catching up on all these reviews after exams, so it's been months since I finished the books.

The Philadelphia Chromosome by Jessica Wapner chronicles the discovery of Gleevec, the drug that's turned Chronic Myelogenous Leukemia from a fatal to a chronic condition people live with for decades. 

The first part is about the biology of cancer and Chronic Myelogenous Leukemia specifically. There are some interesting parts, like the discovery of the translocation between chromosomes 9 and 22 that created the fusion oncoprotein BCR-ABL, and how this was seen in the microscope and the protein was discovered using immunoprecipitation. She also talked about the study of cancer-causing viruses like the Rous Sarcoma Virus and how these gave researchers a clue that cancer was a genetic disease. I did like learning a bit about the history, about how the researchers did it, but unfortunately it did feel very dumbed down in terms of the actual science. 

When she talked about the central oncoprotein that's the distinguishing feature of CML, she definitely dumbed it down which was annoying since I've covered them in college. Now maybe I'm not the target audience but it was still very frustrating to see the tyrosine kinase described as 'powering up' a protein [or whatever her exact words were] when what it does, adds a phosphate group to a tyrosine residue, isn't actually that complicated, especially if you use diagrams. I understand why she did it like that but I'm just reviewing it in terms of my own experience reading it. If you're less interested in the biochemistry e.g. if you're reading it as a patient or family member of one, as many people do, then it might work for you.

In the next part, Wapner talked more about the process of discovering Gleevec and the various scientists who spearheaded it, especially Brian Druker. Druker was originally a doctor and apparently got sick of not being able to help his patients, so became a scientist to find a treatment. There was a lot of talk about other scientists and their various movements between labs that I've forgotten but basically it amounted to finding a drug that would combat the overactive BCR-ABL fusion protein (tyrosine kinase) in test tubes, and then bringing that to market via a pharma company. It was a long journey, from getting something that worked in a test tube to trying out different formulations of it, figuring out how to industrially produce it, figuring out how to make it digestible so it could be taken orally, and doing toxicity testing on various animals after doing them on human cells in a test tube. The drug showed some liver toxicity in dogs(?) and there was a huge amount of pushback from the pharma company, partly because CML is quite a rare disease so it mightn't be super profitable, but eventually it got through and into clinical trials. 

Once it was finally in clinical trials, people were (pretty much literally) dying to get into them. They were testing the new drug against a competitor (IIRC) and Gleevec worked so well that they ended up switching everyone onto Gleevec because it was cruel to let people continue on a clearly inferior drug. The drug also had a good safety profile and people could take it up to quite high doses. 

When the drug went to market it was a huge success story; CML used to be a (slow) death sentence most of the time, but now people live normally with it and just take a pill, some derivative of Gleevec the tyrosine kinase inhibitor, every day.

CML was an interesting case because it's usually caused by the chromosomal translocation that creates the BCR-ABL fusion protein, resulting in an increased number of white blood cells until the person eventually goes into a painful 'blast crisis' and dies. Previously a major treatment for it was interferon, which gave the person symptoms of flu for as long as they were taking it and basically made their lives hellish with lots of physical flu symptoms and depression and fatigue. It also stopped working eventually and the person would progress to blast crisis. So Gleevec was pretty great. People want a 'Gleevec for every cancer' but unfortunately that won't be so easy because CML is special in having that very specific, targetable fusion protein which means it can be killed without harming normal cells. It was definitely a boost to looking at cancer as a genetic disease and figuring out how to treat it from there, though.