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Sunday, December 7, 2014

The Koyal Group Info Mag Review P53: The Gene That Cracked the Cancer Code by Sue Armstrong – review

“A cure for cancer” – the phrase is so often repeated, surely it must finally materialise? To anyone not familiar with the developing story of cancer research, the position seems tragically unsatisfactory. Billions of pounds and decades of work by thousands of researchers have produced much better prognoses for some cancers, but harsh forms of chemotherapy and radiotherapy are still the standard treatment and the much sought-after magic cure remains tantalisingly out of reach.

As Sue Armstrong points out at the beginning of her book, while we may naively wonder why so many people get cancer, researchers are asking “Why so few?”. Every time a cell divides – skin and digestive-tract cells are constantly proliferating – there is a possibility of genetic errors. For cancer to develop, it requires the control mechanism in just one cell to be thrown into disorder, resulting in unlimited replication of that rogue cell. Considering the stupendous number of cell divisions occurring in the human body the development of cancer is rare. Scientists have long suspected that there is a very powerful protective mechanism at work.

P53 (the name refers to a protein of molecular weight 53 kilodaltons) is the cancer prophylactic for most multicellular organisms; it has been dubbed the guardian of the genome. While cancer has many causes and can be insidiously malignant throughout the body, p53 is the single most unifying factor in the disease: for most kinds of cancer to develop, p53’s suppressor activity has to have been disabled.

It has taken scientists a long time to establish some of the basic facts about cancer. In 1911 the pathologist Peyton Rous reported a virus that caused cancer in chickens. For decades this finding was dismissed: cancer, according to the official line, could not be caused by a virus. Rous lived long enough to see Francis Crick and James Watson’s double helix structure of 1953 establish DNA’s role at the heart of life and for his own theory to be subsequently vindicated; he received the Nobel prize in 1966 for his pioneering work.

How did we come to probe these minute molecular workings of nature? Most popular texts on genomics and molecular biology blithely report the results without offering any insight into how the scientists have reached their conclusions. Armstrong’s book has one of the best accounts I’ve read of how science is actually performed. She asks, what can they actually see? When it comes to a gene, which is only two nanometres wide, the answer is “nothing”; they work by inferring from experiments on things that they can see. As she says: “It is the ‘unseeable’ nature of molecular biology … that makes it so difficult to grasp.” She quotes one of her scientists, Peter Hall: “it’s based on faith, ultimately.” And even when scientists have a good sense of what their experiments are telling them, they’re up against the fact that life is an immensely complicated process: we can land a probe on a distant comet after a 10-year flight because the Newtonian clockwork of bodies in space is predictable. But all-embracing laws of biology are hard to find.

The process of discovery goes like this (and p53 is a classic example): something unexpected and odd turns up; investigation begins; its character gradually becomes clearer but its purpose remains a mystery; then evidence accumulates to suggest a function. That evidence is often misleading and, in the case of p53, a function diametrically opposed to the true one was ascribed to it for 10 years: it was thought to be a cancer-causing protein. Then came the moment of clarity and the potentially great unifying principle was born: in 1989, P53 was revealed as the master tumour suppressor – an order was established at last.

There are great hopes that our knowledge of p53 will lead to novel cancer treatments, but the pattern has grown much more complicated since then. In some situations p53 can cause cancer. For cancers to grow they need a mutated and disabled p53: in science, these cycles of discovery go on forever, and so will the battle between cancer and p53.

But progress is being made. One of the brightest hopes for therapy using p53 is in families with a predisposition to cancer. The reason for this blight is that the family members have each inherited a mutant copy of p53 and are therefore without the normal protection it provides. An experimental gene therapy (Advexin) already exists to correct this, but in 2008 the US regulatory body refused to license the treatment. A similar product, Gendicine, is licensed in China and approval for its clinical use is being sought in the US. One common story in today’s medical research is of remarkable possibilities constantly being blocked by a sluggish regulatory system and the skewed priorities of Big Pharma, which prefers to develop bestselling drugs that will have the widest use.

Armstrong’s book will offer many readers a sense of hope, but might also induce intense frustration at the long time it takes for discoveries in the lab to filter down to hospitals and the marketplace. Nevertheless, we can be sure that p53, even if it is not the “cure for cancer”, will have an honourable role to play in our attempts to find one.

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