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Even though they are much bigger, elephants are much less likely to get cancer than mice - or humans (Source: John Lund/Getty Images)

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The gene that fights cancer

Tuesday 27th October 2015 8:32 am

Way back in the last century, in 1975, Richard Peto, a young statistician at the University of Oxford drew attention to a statistical mystery.

He proposed Peto’s paradox — why do we humans suffer from so few cancers?

At this stage, you will quite rightly point out that we get lots of cancers. One in every three of us will grow some kind of a cancer at some stage in our lives, and unfortunately, about one in every five of us will die from a cancer.

But compare humans to mice. We are a lot bigger than mice, and we live a lot longer. If you work out the numbers, human cells divide about 10,000 times more often than mice cells. Whenever a cell divides, there’s a chance of a mistake in the new DNA — and also, an extra chance of a cancer. And yet, both humans and mice have the same lifetime risk of getting a cancer — even though the statistics say that we should have 10,000 times more cancers.

And if you scale up to elephants, which are both long-lived and huge, they should be dying from colon cancer at the age of three.

But exactly the opposite is true. Elephants are somehow ‘protected’ from cancers. Only one in 20 elephants dies of a cancer — even though they weigh 100 times more than we do. And their bigger elephant body is made of lots of extra cells, which undergo lots of extra cell divisions.

Four decades later, we might be close to solving Richard Peto’s paradox. The answer seems to be related to a protective gene called p53 — which, among many other activities, would appear to help fight cancer. While we humans have one copy of p53, elephants have 20 copies.

In fact, there are humans who don’t even have one good copy of this p53 gene. Humans suffering from a rare condition called Li-Fraumeni syndrome have only a defective copy of the p53 gene. They usually get a cancer in childhood, and their lifetime risk of getting a cancer is close to 100 per cent.

The p53 gene makes a chemical also called p53. It was discovered back in 1979 by David Lane and colleagues. It got its name because it was a protein, and it has a molecular weight of 53,000. (For comparison, that’s about 10 times heavier than an insulin molecule.)

It’s a very famous molecule — p53 has had over 15,000 papers published about it, and in 1993, was elected ‘Molecule Of The Year’ by Science magazine.

This molecule, p53, is often called the guardian of the genome. It protects our DNA. Inside the human body, it has God-like properties — it decides if a cell is to live, or die.

When damage to the DNA is detected, it springs into action and joins up with three other molecules of p53. Then the group of four will try various actions.

First, it will try to repair the damaged DNA — sometimes it can, but sometimes it cannot. When it can’t fix the DNA, the p53 complex can force the cell to commit suicide. This ability to force damaged cells to die is one way that p53 protects us from cancer.

Mind you, this powerful guardian can go wrong all by itself. And furthermore, we humans can damage the p53 gene with cigarette smoke and ultraviolet light.

Today, we know that about half of all human cancers show some kind of mutation in the p53 gene. A few preliminary studies have shown that repairing the p53 gene eliminated some cancers. Another therapy involved leaving the faulty p53 gene in the DNA alone. Instead, it concentrated on repairing the faulty p53 protein — and this therapy had some success. Another (and more subtle option) is to bypass the p53 gene and the p53 molecule completely — and instead, go to the processes that the p53 molecule activates, and switch them on.

Mind you, there is a down side. The p53 molecule can limit cancer — and unfortunately, it can accelerate ageing. One pathway of ageing is that we lose the ability to repair and regenerate damaged cells. More specifically, we run out of the stem cells that can do this repair and regeneration. And why do we run out of stem cells? Because these stem cells have become damaged, and then forced to commit suicide by the p53 response pathway.

But if our scientists can understand the incredible subtleties with which p53 operates, we might be able to, like elephants, both live longer and avoid cancers.


This blog first appeared on Dr Karl's Great Moments in Science

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