So just how did James Bond, Moby Dick and the London Natural History Museum teach me about oncology in clinical trials and tumor behavior? Here’s my story. As a child I loved wandering through the London Natural History Museum (NHM). It was fascinating to experience the natural world through its exhibits which was made all the more exciting, knowing these corridors had housed the research and development department of covert operations of the SOE (Special Operations Executive) during the Second World War. Legend has it that the real life director of the department was the inspiration for the character “Q” in Ian Fleming’s James Bond series.
The NHM has now added a modern five story annex named the Darwin Center which is dedicated to the life sciences and works to enhance the public understanding of science. In the mid 1970’s, the exhibits on Evolution and Darwin’s work were relegated to one of the darker and more remote galleries of this Gothic Victorian building.
Principles of Tumor Behavior and Biology
Understanding evolution had become an obsession in the manner of Captain Ahab’s quest for the great white whale. Thankfully the cause was not a sadistic biology teacher but the inability to grasp the concept that explains the panorama of life. I think my mother, a biologist, despaired of me! I’m glad I persevered because much of tumor behavior and biology can be explained via its principles(1). For example, drug resistance can be explained on the basis of three principles:(2-4)
- Individual variation exists in the population
- Variations are heritable
- Variations in individuals lead to differential survival and reproduction (2)
In other words, it is possible to select out resistance in tumor cell populations by the very act of treatment. By chance a random clonal cell line will develop or inherit a genotype that allows it to survive in the harsh environment of a tumor under treatment. Resistance mechanisms don’t possess intelligence but respond through pathway modulation that is rarely predictable. In fact, the presence of several clonal proliferations mediated by evolutionary mechanisms has been demonstrated in individual tumors (4).
Imaging in Tumor Behavior
Biopsy sampling becomes a real problem in the presence of spatially distinct colonies. Imaging of course has the distinct advantage of being non-invasive and probing the live organism rather than sampled tissue. Limitations of course exist. Clinical modalities cannot resolve microscopic processes. This is the realm of molecular imaging which promises increased resolution and sensitivity beyond the length scales of current scanning equipment.
In 1859 Darwin proposed an interpretation of life based on natural selection. So far, no scientific data have reliably refuted observation. Rather it continues to eloquently explain the complex behavior of cancer. My thanks to Ian Fleming, Herman Melville and a dark forgotten corridor in the NHM that has me entertained for 30 years!
Sources:
- Greaves M. Darwinian medicine: a case for cancer. Nat Rev Cancer 2007;7(3):213-221.
- Gerlinger M, Swanton C. How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine. Br J Cancer 2010;103(8):1139-1143.
- Casanovas O. Cancer: Limitations of therapies exposed. Nature 2012;484(7392):44-46.
- Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366(10):883-892.
