Matt Ridley

You can now see why detecting cancer early in the development of the tumour is so important. The larger a tumour becomes, the more likely it is to suffer the next mutation, both because of general probability and because the rapid proliferation of cells inside the tumour can easily lead to genetic mistakes, which can cause mutations. People who are especially susceptible to certain cancers often carry mutations in 'mutator' genes, which encourage mutation generally (the breast cancer genes BRCA1 and BRCA2, discussed in the chapter on chromosome 13, are probably breast-specific mutator genes), or because they already carry one faulty version of a tumour-suppressor gene. Tumours, like populations of rabbits, are prone to rapid and strong evolutionary pressures. Just as the offspring of the fastest-breeding rabbits soon dominate a rabbit warren, so the fastest dividing cells in each tumour come to dominate at the expense of more stable cells. Just as mutant rabbits that burrow underground to escape buzzards soon come to dominate at the expense of rabbits that sit in the open, so mutations in tumour-suppressor genes that enable cells to escape suppression soon come to dominate at the expense of other mutations. The environment of the tumour is literally selecting for mutations in such genes as the external environ-D E A T H 2 3 7

ment selects rabbits. It is not mysterious that mutations eventually show up in so many cases. Mutation is random, but selection is not.

Likewise, it is now clear why cancer is a disease that very roughly doubles in frequency every decade of our lives, being principally a disease of old age. In somewhere between a tenth and a half of us, depending on the country we live in, cancer will eventually get round the various tumour-suppressor genes, including TP53, and will inflict a terrible and possibly fatal disease upon us. That this is a sign of the success of preventative medicine, which has eliminated so many other causes of death at least in the industrialised world, is little consolation. The longer we live, the more mistakes we accumulate in our genes, and the greater the chance that an oncogene may be jammed on and three tumour-suppressor genes jammed off in the same cell. The chances of this occurring are almost unimaginably small, but then the number of cells we make in our lifetimes is almost unimaginably large. As Robert Weinberg has put it:5 'One fatal malignancy per one hundred million billion cell divisions does not seem so bad after all.'

Let us take a closer look at the TP53 gene. It is 1,179 'letters'

long, and encodes the recipe for a simple protein, p53, that is normally rapidly digested by other enzymes so that it has a half-life of only twenty minutes. In this state, p53 is inactive. But upon receipt of a signal, production of the protein increases rapidly and destruction of it almost ceases. Exactly what that signal is remains shrouded in mystery and confusion, but damage to D N A is part of it. Bits of broken D N A seem somehow to alert p53. Like a criminal task force or S W A T team, the molecule scrambles to action stations. What happens next is that p53 takes charge of the whole cell, like one of those characters played by Tommy Lee Jones or Harvey Keitel who arrives at the scene of an incident and says something like: ' F B I : we'll take over from here.' Mainly by switching on other genes, p53 tells the cell to do one of two things: either to halt proliferation, stop replicating its D N A and pause until repaired; or to kill itself.

Another sign of trouble that alerts p53 is if the cell starts to run 2 3 8 G E N O M E

short of oxygen, which is a diagnostic feature of tumour cells. Inside a growing ball of cancer cells, the blood supply can run short, so the cells begin to suffocate. Malignant cancers get over this problem by sending out a signal to the body to grow new arteries into the tumour - the characteristic, crab-claw-like arteries that first gave cancer its Greek name. Some of the most promising new cancer drugs block this process of 'angiogenesis', or blood-vessel formation.

But P53 sometimes realises what is happening and kills the tumour cells before the blood supply arrives. Cancers in tissues with poor blood supply, such as skin cancers, therefore must disable TP53 early in their development or fail to grow. That is why melanomas are so dangerous.

Little wonder that p53 has earned the nickname 'Guardian of the Genome', or even 'Guardian Angel of the Genome'. TP53 seems to encode the greater good, like a suicide pill in the mouth of a soldier that dissolves only when it detects evidence that he is about to mutiny. The suicide of cells in this way is known as apoptosis, from the Greek for the fall of autumn leaves. It is the most important of the body's weapons against cancer, the last line of defence. Indeed, so important is apoptosis that it is gradually becoming clear that almost all therapeutic cancer treatment works only because it induces apoptosis by alerting p53 and its colleagues. It used to be thought that radiation therapy and chemotherapy worked because they pref-erentially killed dividing cells by damaging their D N A as it was being copied. But if that is the case, why do some tumours respond so poorly to treatment? There comes a point in the progression of fatal cancer when the treatment no longer works - the tumour no longer shrinks under chemical or radiation attack. Why should this be? If the treatment kills dividing cells, it should continue to work at all times.

Scott Lowe, working at Cold Spring Harbor Laboratory, has an ingenious answer. These treatments do indeed cause a little D N A damage, he says, but not enough to kill the cells. Instead, the D N A damage is just sufficient to alert p53, which tells the cells to commit suicide. So chemotherapy and radiation therapy are actually, like D E A T H 239

vaccination, treatments that work by helping the body to help itself.

The evidence for Lowe's theory is good. Radiation, or treatment with 5 -fluorouracil, etoposide or adriamycin - three chemical cancer treatments - all encourage apoptosis in laboratory cells infected with a viral oncogene. And when hitherto tractable tumours relapse and suddenly fail to respond to treatment, the change correlates closely with a mutation knocking out TP53. Likewise, the most intractable tumours - melanoma, lung, colorectal, bladder and prostate - are the ones in which TP53 is usually mutated already. Certain kinds of breast cancer resist treatment: the ones in which TP53 is broken.

These insights are of great importance to the treatment of cancer.

A major branch of medicine has been acting under a large misappre-hension. Instead of looking for agents that kill dividing cells, doctors should have been looking for agents that encourage cell suicide.

That does not mean chemotherapy has been wholly ineffective, but it has been effective only by accident. Now that medical research knows what it is doing, the results should be more promising. In the short term it promises a less painful death for many cancer patients. By testing to see if TP53 is already broken, doctors should soon be able to tell in advance if chemotherapy will work. If it will not, then the patient and his or her family can be spared the suffering and false hope that is now such a feature of the last months of life for such people.7

Oncogenes, in the unmutated state, are needed for cells to grow and proliferate normally throughout life: skin must be replaced, new blood cells generated, wounds repaired and so on. The mechanism for suppressing potential cancers must allow exceptions for normal growth and proliferation. Cells must frequently be given permission to divide, and must be equipped with genes that encourage division, so long as they stop at the right moment. How this feat is achieved is beginning to become clear. If we were looking at a man-made thing, we would conclude that a fiendishly ingenious mind must be behind it.