Tuesday, June 18, 2013

The Philadelphia Chromosome

The book by Wapner, The Philadelphia Chromosome, is simply perfect. It is a wonderful balance of science, personalities, inventions and medicine. It flows smoothly, giving the reader the opportunity to catch up each time a new step is taken. The topic is simply the best example of how we are beginning to understand cancer in a detailed manner, thus allowing us to develop therapeutics to treat cancer, turning many from death sentences to chronic disease. The focus of Wapner’s book is CML, chronic myelogenous leukemia. This is a blood cancer where the white cells start changing and slowly increase and then in a blast crisis cause total collapse and death. This is the story of how it was understood what caused it and how to stop it.

She takes the discovery of the Philadelphia chromosome and walks the reader step by step to the acceptance and use of imatinib. I remember a colleague in Vienna, Austria, who in 2002 came down with CML, at a young age, and I had been following the imatinib development and after a few calls it was possible to get him on the therapeutic and he survived. This tale has some many coincidences, most positive, that makes its telling almost mandatory to best understand where cancer therapeutics is progressing today.

The tale presented by Wapner is fairly straightforward; it is a mixture of science, luck, coincidence, and human nature.

The first part of the book takes us from the early 1950s through the mid-1980s, where we go from not understanding to having a somewhat clear scientific comprehension of both the problem and a remedy. The first part moves through the following:

1. Using an innovative way to look at chromosomes the 1959 discovery of a chromosomal alteration indicates that a hematological cancer, CML, presents with this abnormality. A short end on one chromosome and longer end on another were observed. This is just six years after the Watson and Crick paper.

2. Recognition of a cancer generating gene.

3. Recognition of the fusion of two chromosomes

4. The understanding of how protein kinases work via the src gene from chicken sarcomas. In fact on p 47 the author describes this process and she does a superb job in highlighting what will become a significant key in the overall development of imatinib.

5. The discovery of the Abelson gene, abl, and its relationship to cancer. On p 63 the author relates how Abelson was berated in 1969 by physicians and the president of AACR, the cancer research society. Frankly at that time cancer was the realm of the surgeon, who often just cut as much as possible and often doing more damage than good.

6. The new Gag/Abl protein, namely the fusion seen on chromosomes is identified as the fusion of two genes. The author on p 72 has a wonderful description of this insight.

7. Gag/Abl causes cancer. On p 83 the author discusses the work in David Baltimore’s lab in the early 80s. At the same time they found abl had come from chromosome 9 and was transported to chromosome 22 attached to gag.

8. The tale of Drucker and his persistence and dealings with Ciba Giga, eventually to be Novartis starts at this point. Here we see the drive of pushing, connecting, developing, and frankly persevering with a positive result. It was recognized that the Gag/Abl fusion product was the driver of CML and that the driver of that was ATP and ATP found a connection point on the protein. Then if a new molecule could bind and block the ATP the gene effects, namely cancer, could be blocked. Thus starts the second part of the book.

The second part of the book is much less linear and shows the complexity afoot in the pharma world. Even though Drucker, and at this point many others, saw the path forward, it was necessary to engage the pharmas and their massive powers as well as their bureaucracies. Thus, we have the tale of this part. The author does a superb job of giving some light on the development and testing of therapeutics. One walks away seeing the most bureaucratic part the pharma and the FDA and Government entities almost acting as sideline players at best.

The infighting in the pharmas, the conflicts between development, marketing, toxicology, and management is a wonderful tale, typical of so many large institutions. The lesson from part one is the brilliance of the dedicated researchers, that from part two is one wonders how any therapeutic is ever developed. In today’s world it would take fifty years to approve aspirin!

Wapner’s book presents great history but it begs the question of the future progress. Although that was not the intent of Wapner, she sets up the question quite nicely. She shows how research and development proceeded from the 1950s through the end of the century. I would argue that we are at the beginning of a new paradigm of development, and it is not clear if the institutions are all that prepared to deal with it.

There are several drivers which make the future even more interesting.

First the communications over the period of 1959 through 2002 were driven most often by personal contact, journals and conferences. Today the Internet spreads results and data around the world instantaneously. The chance occurrences are increased orders of magnitude.

Second, as we look at kinases we now understand them first as intracellular networks and pathways and secondly as distributed spatio-temporal systems. This means that we are moving from the world of bench researchers and their singular focus to the “engineer” and their systematic approaches. Cancer is viewed as an unstable multidimensional system. Fortunately there are many tools and expertise to deal with such a paradigm.

Third, and this is an exceptionally critical change, we have multi-national participation, with explosions from countries like China.

One is starting to see more and more of the fundamental work arising from not just the US and Europe but Asia. These three factors will most likely be accelerators for the tale told by Wapner. However she also contains the cautionary tale of the Pharmas and the regulatory bodies, oftentimes the brakes on progress. That will most likely be the challenge to realizing true progress on cancer.

The future may very well be driven by the observations of Eddington and Einstein:

“It is also a good rule not to put too much confidence in the observational results that are put forward until they are confirmed by theory.”  Arthur Eddington

“It is quite wrong to try founding a theory on observable magnitudes alone. It is the theory which decides what we can observe.” Albert Einstein

The two quotes frame the changes which are occurring in the understanding of cancer. The tale by Wapner was initially data driven, there was not model, it had to be constructed. Now, we have models, we understand pathways, we understand where they fail, and thus result in cancers. We have the models and thus hopefully we can make better and faster sense of the data. Wapner sets the path to best understand that progress.