Flipping the switch: The physiology of Cancer

The final few chapters of The Emperor of All Maladies faces the problem of understanding carcinogenesis – the initiation of cancer formation. Before the discovery of cancer-causing genes, scientists pondered the origins of cancer. Ideas ranging from black bile to viruses surfaced within the scientific community. The general consensus was that cancer was caused by an external factor, outside the body, such as a virus or bacteria. It would take a remarkable discovery and persistent scientific research to uncover the true cause. One virus known to cause cancer was the Rous sarcoma virus, which causes cancer in chickens. This was the preliminary discovery which paved the way to the modern theory.

This virus is a strange one. It disobeys the ‘central dogma’ of biology, that is, the flow of genetic material within cells. Usually, we begin with DNA, which is copied into another smaller form of genetic material called RNA, in trans. This RNA then attaches onto proteins (r
ibosomes)
which act as a molecular machine, spewing out amino acids which go on to create proteins.

However in this virus, the flow of genetic material operates in the opposite direction. Firstly, the virus (which consequently only contains 4 genes compared to the 25,000 of the human genome) has an RNA copy of its genes. When the virus infects a cell, it injects its RNA into the nucleus. The virus also contains one vital protein: the reverse transcriptase enzyme. This enzyme is capable of converting the RNA back into DNA, contrary to transcription as shown in the diagram, hence the name reverse transcriptase. The newly formed viral DNA is then inserted into the chromosomes of the host cell. This DNA now acts as a blue-print to code for all the necessary vial proteins (enzymes, protein coat etc) to make more and more copies of the virus. As the cell carries out its normal functions, it unknowingly and willingly synthesises all these proteins which assemble into the rous sarcoma virus.

Any virus that works in this way is called a retrovirus. On a molecular level, how does the RSV cause cancer? Out of the 4 genes of this virus, one is the scr gene. This codes for the production of a particular protein, more specifically a mutated protein kinase enzyme. This enzyme is responsible for attaching phosphate groups to certain molecules, which in turn functions as an  “on or off” switch for many other cellular activities. When this virus infects a host cell, the process of turning activities on and off goes into hyper drive. The mutated kinase enzyme is stuck permanently in the “on” position. Eventually, switches relating to mitosis (cell division) may be switched on, leading the cell on an unstoppable path of chaotic division, creating tumors which spread to other parts of the body.

This is how the rous sarcoma virus causes cancer, but what about the countless other carcinogenic compounds such as cigarette smoke, asbestos and chimney soot? Once the mechanism of the RSV was unravelled, scientists began to search for identical genes to scr in a multitude of other animals. To their surprise, this gene appeared in all animals, even in humans! It turned out that this gene was present in all healthy human cells, and the un-mutated version was responsible for regulating cell division. Thus, when the RSV injects a mutated version into the host’s DNA, cell division becomes uncontrollable.

How did a virus attain a mutated version of a gene found in humans? The theory is that initially, a virus had infected a cancerous cell containing the mutated scr gene. It took up this gene and incorporated it into its own RNA. On infecting other cells, the virus was reproduced and replicated, producing thousands of itself containing this scr gene. Therefore, contrary to the belief held at the time, the cancer wasn’t directly caused by the virus, but rather the virus became cancer-causing after stealing a mutated gene from a human cell. The cancer was there already.

Gradually all research over the past thousands of years began to fall into place. What if cancer wasn’t caused by an exogenous factor? What if the cancer came from within the cell rather than from a virus or external influences? This radical idea turned out to be right.

So, from this discovery, carcinogenesis was born. Within cells, there are over 25,000 genes. Some of these genes are responsible for producing proteins involved with mitosis. If there is a mutation in a gene which codes for, lets say, mucus production (CFTR) then you end up with cystic fibrosis. However if a mutation occurs in a gene involved with cell division, then masses of new cells are manufactured, resulting in a cancer. A molecular ‘switch’ is flipped on in DNA, which make certain proteins, and as a result they produce endless copies of themselves as if the “accelerator has been jammed”.

Genes related to cell division or even cell death are called proto-oncogenes. If a mutation occurs in one of these genes, it turns into an oncogene. This can lead to uncontrolled cell proliferation and eventually to a cancer. Since the discovery of the first oncogene, scr, many others have been discovered.

And to leave you with a thought, it isn’t just genes controlling mitosis which, if mutated, can lead to cancer. Other genes which produce proteins which suppress cell growth, if mutated, can also lead to cancer. Can you figure out how this works?

http://carcin.oxfordjournals.org/content/36/9/937.abstract

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