One medicine: an introduction.

All of nature has inherent value for biology. Consider how much we have already learned from the comparative biology of yeast,worms, flies, zebra fish and many other diverse organisms about the molecular machinery governing normal cell division and normal growth and development; knowledge that applies also to mammals. Plant systems have advanced our understanding of epigenetics that might also apply to cancer biology. Aberrations in these basic processes such as the cell cycle check points and chromosome alignment on the mitotic spindle contribute, of course, to cancer. Naturally occurring oncogenic retroviruses associated with tumors in animals – mainly domesticated chickens, mice and cats, gave us our first glimpse, about 30 years ago, of oncogenes, cellular genes highly conserved throughout mammalian evolution. I experienced the excitement of this era by helping to discover two oncogenes, both cytoplasmic tyrosine kinases (see below) in spontaneous sarcomas of domestic cats. In studying retroviruses in wild mice as a potential model for human cancer, I also learned the importance of natural history knowledge in contrast to the information gained from laboratory mice. In the 1980s, DNA tumor viruses in animals pointed the way to the key role of evolutionarily conserved tumor suppressor genes with which the viruses interacted and inactivated. In the modern genomic era, we now appreciate that all life forms, and mammals in particular, have evolutionarily related genomes and are governed by similar fundamental molecular processes. We know that oncogenes and tumor suppressor genes, for example, are normal cell genes that function in an intricate network together with many other genes, making up more than 30 signal transduction pathways and protein interaction domains that govern normal cell growth, differentiation and death (apoptosis). Hundreds of oncogenes and tumor suppressor genes and their protein products have already been identified as part of these pathways and domains. Point mutations or altered expression of these genes caused by chromosomal structural abnormalities may contribute to cancer in general and can be detected by modern techniques of cytogenetics, functional genomics and proteomics which allow the near simultaneous analyses of thousands of genes at the RNA and protein levels. Addition to or removal of phosphorous from proteins via protein kinases and phosphatases, respectively, is a key regulator of normal protein interactions in the signal transduction pathways and key driver of many forms of cancer. Immunoassays now permit the detection and quantitation of such intracellular factors and their extent of phosphorylation. Over 500 separate protein kinase genes are encoded in the mammalian genome, but relatively few of their targets are known. However, a good number of these kinases have already been linked to the development of cancer in general and as specific targets of therapeutic intervention. Other genes and proteins involved in signal transduction pathways, such as those controlling chromatin structure, telomere length, RNA transcription, RNA interference, protein folding and stability, cytoskelatal regulation, cell motility and angiogenesis are also highly conserved in evolution. Single nucleotide polymorphisms or larger structural variation in such genes could help explain the familial predisposition to certain cancers. Many other