Saturday, May 31, 2014

Thoughts on Wapner's Philadelphia Chromosome - a great story, explaining the science

I found Jessica Wapner's book the Philadelphia Chromosome a great read. It certainly makes a suitable volume for teaching people about how basic science gets connected to real medical problems, turning into drugs and many complexities along the way. The book starts off, most importantly, with the science, explaining how the key mutation in CML is identified as a fusion involving a tyrosine kinase, the BCR-ABL fusion. It talks about how the idea of oncogenes was developed from the early 1900s, these being aberrant versions of normal genes (proto-oncogenes) in the genome that are disrupted. (For instance, those associated with RSV are disrupted by a virus.) There is a broader discussion of how many of these disrupted genes are kinases, particularly tyrosine kinases, which are involved in many important pathways in the cell.

Then there is a long discussion about chromosomes and translocation and how people realized that the aberrant karyotype in CML actually results from a particular chromosomal translocation and how this effects the location encoding the BCR and ABL genes, connecting up two lines of research. There is much discussion of the historical figures involved including the Nobel Prize winners Bishop, Varmus and Baltimore and many of their protégés.

After the aberrant tyrosine kinase BCR-ABL was identified, Wapner goes through the long story of how a drug company (Novartis) actually sets about to create a compound to deal with this and how arduous that is. She leads us through the phase I, phase II and phase III trials of the drug, initially called STI-571. She describes how it had to just demonstrate efficacy relative to the conventional treatment for CML (Interferon), how it did so well and how it was fast tracked into patients, there being so much demand. Initially the drug company was a little reluctant because of the small market for CML, preferring to go forward with tyrosine-kinase targets associated with more common diseases such as breast cancer.

Finally, Wapner talks about some of the interesting corollaries of a successful drug trial, including: the development of resistance in cancers (based on particular mutations in Abl and how the companies have developed alternate tyrosine kinase inhibitors to combat these), how there has been lots of interesting downstream science to understand BCR-Abl in more detail, such as a crystal structure of the kinase, and how economically Novartis actually ended up doing much better from this "niche disease" than expected, since CML patients are living much longer than their initially supposed few months.

Overall I found this a very good read that really puts science in context and I would recommend it highly for introductory classes that want to associate a lively story and names of particular people with abstract scientific ideas.

My tags: "Gettysburg Tryptophan Philadelphia" and
The Philadelphia Chromosome: A Mutant Gene and the Quest to Cure Cancer at the Genetic Level
by Jessica Wapner