In 1971 president Richard Nixon and the US Congress declared a war on cancer. Since then the federal government has spent more than €80 billion fighting the disease, and probably as much again has been spent in the rest of the world. Despite this effort, there has been little overall progress: the cancer death rate has decreased by only 5 per cent in the US since 1950 (Gina Kolata, New York Times, April 24th, 2009). Why is this? The main reason seems to be that cancer has turned out to be much more complicated than scientists thought. The story is told by George Johnson in the Scientific American (November 2013).
Cancer is a group of diseases characterised by the uncontrolled growth and spread of abnormal cells. It is the second leading cause of death in Ireland, after heart disease, accounting for 25 per cent of the annual death toll, but much progress has been made in combating heart disease. Deaths from cardiovascular disease in the US fell by 52 per cent between 1975 and 2006.
The chemical nature of the genetic material in the cell is the long double-helical molecule DNA. A DNA molecule is made of many smaller molecules called nucleotides, strung together end to end. There are four nucleotides, denoted by the letters A, T, G and C. DNA contains the genetic information as a chemical code in the form of the sequence of these four letters. A mutation occurs when this information is altered, for example by a deletion of one or more letters.
The information in DNA is divided into chunks called genes. The information in one gene codes for a single protein in the cell, and proteins are the agents that carry out the cell’s activities. A mutation in a gene will alter an activity in the cell.
In a paper called The Hallmarks of Cancer published in the journal Cell in 2000, Douglas Hanahan and Robert Weinberg outlined the modern interpretation of how cancer develops. They said cancer is born when a single cell acquires a genetic mutation that starts it down the cancer road. Subsequent mutations accumulate until the cell becomes unambiguously cancerous, multiplies out of control and develops into a tumour.
New discoveries
However, since that Cell article, new discoveries in biochemistry and cell biology have shown that the molecular biology of the cell is much more complicated than previously thought, and we now know that cancer can be initiated in more ways than by genetic mutations.
DNA does not exist in the cell as a “naked” double helix but is associated with special proteins called histone proteins and is also tagged on its surface with chemical groups called methyl groups. These proteins and methyl groups exert a regulatory effect on the genes, turning their activity up/down or on/off. This regulation of the primary genetic material is referred to as “epigenetic” and must be taken into account, in addition to the more familiar mutations, when pondering the basis for the initiation of cancer. Thus, an increase/decrease in the extent of methylation might turn a gene on/off, as a result of which a cell might be tipped into a phase of unregulated proliferation. Epigenetic effects undoubtedly contribute to cancer but much remains to be discovered about this effect.
Also, much of the DNA in the human genome does not code for proteins. In 2000, when the Cell paper was published, a large fraction of DNA was thought to be a legacy of past evolutionary changes, a legacy that no longer had a function in the cell. It was called "junk DNA". However, we now know that this non-protein-coding DNA does have regulatory functions in the cell, and one can visualise how it could be involved in initiating cancer. Again, the precise contributions made by this junk DNA to the cancer story remain to be elucidated.
The main reason why progress in dealing with cancer is so slow is that the roots of cancer still hide in the fantastic complexity of the cell. I have described only a few aspects of this complexity in this article. It is 42 years since Nixon declared war on cancer. Let us hope it will not be 42 more years before we finally get on top of this devastating disease.
William Reville is an emeritus professor of biochemistry and public awareness of science officer at UCC. understandingscience.ucc.ie
