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The road to cancer: as simple as ATG…

Holly Callaghan

Holly Callaghan

In her shortlisted article for the Max Perutz Science Writing Award 2012, Holly Callaghan, a PhD student at Imperial College London, explains why learning about what goes wrong in the genetic ‘spell checkers’ of cells can help to develop anti-cancer treatments. 

Spelling mistakes — we all make them. Usually a result of carelessness, a ‘g’ might become a ‘c’, an ‘a’ might become a ‘t’. If you’re writing a letter maybe you’ll correct or cross out the offending word, or even scrunch up your paper, throw it away, and start again.

Our cells have a remarkably similar distaste for misspellings. The genetic alphabet is made up of only four letters: A, T, G and C. Cells must diligently copy their DNA, all six billion letters of it, in a precise order so that they can replicate. Some cells, such as skin cells, replicate every half hour, while others, for example brain cells, divide once then never again. Think for a moment about your colon. The surface of this impressive 7.5 metre long digestive organ completely renews every four days — that’s a lot of dividing cells!

Of course, no cell is perfect, and mistakes happen. The enzyme in charge of copying your DNA might copy the wrong letter, or environmental agents like UV light might alter a letter, which can be replicated when the cell divides. But, much like the auto-correction function on your computer, controls are in place to stop these mistakes becoming incorporated into the finished product. DNA repair mechanisms recognise faults and fix them — most of the time. If a mistake is not corrected it will be passed down to the daughter cell. That’s when a simple mistake becomes a mutation.

“But what harm can one little teeny tiny change possibly do?” you might ask. Well that all depends on where it is. The majority of the time the error will occur in ‘junk’ DNA, or DNA which doesn’t code for a gene, so the mutation will quite happily stay with you, doing nothing, for life. The trouble lies in mutations which occur within your genes.

Take, for example, p53 (named because it’s a protein and its molecular mass is 53 — terribly unoriginal). It’s been nicknamed “the guardian of the genome”, due to its role in preventing mutations. As you can imagine, if the gene which codes for p53 becomes mutated then the entire genome of that cell becomes unstable, vulnerable to further mutations.

It will usually take about six mutations in important genes like p53 for a normal cell to become cancerous. This doesn’t seem like a lot, but in reality it is very difficult for a healthy cell to become malignant. The majority of the time, one or two mutations will cause the cell to self-destruct — sacrificing itself for the health of the organism.

The amazing self-renewal capability of the colon is rigorously controlled by special proteins working together in a function known as Wnt (pronounced ‘wint’) signalling. The importance of Wnt signalling is emphasised by the fact that the majority of colon cancers contain mutations affecting this process. These mutations keep Wnt signalling switched ‘on’, sending endless signals for colon cells to grow and divide. Mutations in Wnt signalling may go unnoticed for many years, existing as non-cancerous growths, or polyps. It is only when further mutations accumulate that these small growths become dangerous.

In an average late-stage colon cancer there will be about 75 mutated genes. The majority of these will be inconsequential — mutations that have been picked up by the cell on its journey to cancer but don’t actually contribute towards cancer. These are known as “passenger” mutations. I am interested in identifying “driver” mutations — mutations that directly contribute towards the development of cancer.

The aim of my PhD is to scour the genome of colon cancer looking for mutations. I am concentrating on one gene in particular, a receptor which is known to work alongside the Wnt signalling pathway and encourage the growth of colon cells. I’ve already found a few mutations in this gene in colon cancer samples, and I’m working to figure out what these mutations do and how they contribute to cancer.

How does all of this help in the fight against cancer? If we understand what genetic changes occur in cancer then we can identify new drug targets. For example, a mutation may activate a protein, resulting in it constantly switching on genes that encourage a cell to grow and divide. If this mutation exists in a cell that already contains a background of other mutations, for example in genes that control the self-sacrifice of damaged cells, then the cancerous cell will not self-destruct, but will flourish uncontrollably. If we can create drugs that will inhibit the activated protein then we can slow down the growth of the cancerous cells, or even kill the cancer cells all together.

If I can help identify a drug target that might help treat colon cancer then all this spell checking will be worth it…

Holly Callaghan

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