Saturday, August 05, 2006

The miracle worker - Sunday Times - Times Online

The miracle worker - Sunday Times - Times Online


Feature


The miracle worker
This is p53. The gene keeps cancer at bay, and scientists are racing to find a wonder drug to harness its power. If they get it right, we’ll live longer, healthier, cancer-free lives. If they get it wrong — well, you don’t want to know. Sue Armstrong reports






::nobreak::In 2002 some scientists in Texas who were working with genetically engineered mice made a mistake and got a mighty surprise. In investigating a gene known to be crucial in protecting us from cancer, they created some mice without the gene (so-called “null mice”). The creatures proved highly prone to cancer and developed tumours at an early age, exactly as expected. In another group of mice, the researchers modified the gene, but it turned out rather more active than they intended.

Sure enough, their offspring proved well protected from cancer, as the researchers would have predicted. What nobody expected to
see was that the mice aged exceptionally fast. In just a few months, they looked like very old mice. “They had hunchback spines, ruffled fur, grey hair; things like that,” says Larry Donehower of Baylor College of Medicine in Houston. “And they lived only about two-thirds of their normal life span.” This accidental finding is opening up a new area of research about how this important cancer gene can also modify the ageing process.

People have known for a long time that ageing and cancer are related, in that the chances of getting cancer increase with age. But nobody suspected they might be two sides of the same coin, sharing a common mechanism in which the scales can be tipped either way. In other words, that wrinkled skin, thinning bones and failing organs may be the price we pay in the long run for holding cancer at bay. “We don’t know the full picture yet,” says Professor Sir David Lane of Dundee University, a superstar in the field of cancer genetics, “but it certainly seems there’s a balance to be struck here.”

This discovery has hugely excited scientists studying both cancer and ageing, who have begun to collaborate seriously for the first time. “The clinical implications are clear,” says Lane. “People are beginning to ask, ‘Can I manipulate the system to get the best of both worlds?’” But the discovery raises other, more immediate – and alarming – questions. Could existing treatments for cancer, which often stimulate the activity of this important gene, accelerate ageing in the patient and lead to age-related disorders, such as dementia, later on? Or, conversely, could the use of drugs to try to slow the effects of ageing in people put them at higher risk of cancer? In meddling with genes without fully appreciating what might result, are we playing with fire? Nobody yet knows.

The gene at the centre of this flurry of interest is known simply as p53, because 53,000 is the molecular weight of the protein the gene produces when it is active. (Genes are, in effect, just recipes for proteins, which do all the work in our cells. The proteins are made only when and where they are needed, at which point the relevant gene is “switched on”.) P53 functions as a tumour suppressor. It senses when the DNA of a cell – the material inside the cell’s nucleus that carries all the genetic information – has been damaged. It can either stop the unnatural cell from reproducing itself – as it’s programmed to do in the normal course of body maintenance – until the DNA is repaired, or it may induce “cell suicide”. Nicknamed by Lane “the guardian of the genome”, because of its vital role in seeing that cells with scrambled DNA aren’t allowed to replicate and set off on the road towards cancer, the gene is found to be mutant and useless in more than half of all human tumours. Thus, while all cancers are caused by faulty genes, mutant p53 is the single most common genetic fault of all (see the graph on page 21).

Once the role of p53 was recognised, hundreds of molecular biologists worldwide dropped their own projects and took up with this little gene, beguiled by the prospect of conquering cancer – a disease you and I have a one-in-three chance of suffering from at some point in our lives, and a one-in-four chance of being killed by it. P53 has become the most widely studied single gene in history, generating nearly 36,000 published papers to date and bringing together every two years an ever-widening community of scientists working on the frontiers of cancer research to share their latest findings on the gene.

Like so many great scientific discoveries, p53 was found by accident in the late 1970s. When the protein made by the active gene cropped up unexpectedly in laboratory experiments looking at the activity of a monkey virus that causes tumours, most researchers dismissed it as an irritating contaminant. However, David Lane, then doing a post-doctoral fellowship in cancer research in London, was intrigued. The “rogue” protein appeared so regularly in his experiments, and he was so sure he had avoided contamination, that he felt compelled to find out what it was. His discovery that the “rogue” protein was a key player in the cancerous cells he was investigating was the cover story in Nature in 1979. Papers from other researchers, most notably Arnold Levine of Princeton University, New Jersey – who made the same discovery of a protein active in tumour cells – followed quickly. Scientists have learnt a great deal about how p53 works, which is essentially to orchestrate a cascade of events in response to cellular stress.

Conditions such as low oxygen or nutrient levels within cells, overexposure to sunlight and radiation, as well as DNA damage, send out alarm signals that switch on p53. The p53 then activates a series of genes “downstream” that put the brake on cell division, or induce cell suicide – a process known as “apoptosis”, from the Greek meaning “to drop out” and used poetically to describe the shedding of autumn leaves. (Researchers say this is what the dead cells scattered among the living in human tissue look like under the microscope.)

In 1992, impatient to find out whether what scientists were learning in the lab is what actually happens in us, Lane and Peter Hall, a cancer specialist and fellow p53 researcher, cooked up a maverick experiment over a pint in a Dundee pub, using Hall as the guinea pig. The experiment involved subjecting Hall’s arm to radiation from a sun lamp – “equivalent to 20 minutes on a Greek beach” – and taking a series of time-staggered skin biopsies to watch the activity of p53. “We reckoned that if this gene does respond to stress in living organisms, we should see the accumulation of p53 protein in the cells in my radiated skin. And that’s exactly what we did see,” says Hall, rolling up his sleeve to reveal nine neat scars. “We did the experiment on me because we wanted quick results. It would have taken months to get a licence for animal experiments. The scars all got infected,” he laughs, “but the experiment worked brilliantly, and it moved the field on considerably.”

The sun-lamp session was enough to trigger p53 but not damage the DNA and, as anticipated, Hall and Lane saw the protein level subside in time without causing cell arrest or apoptosis. They observed the normal functioning of p53 as it surveys our cells for signs of trouble. When the gene is unable to do its policing job, cells are at risk of becoming cancerous. Most often this is because p53 is damaged by mutation. There is a rare condition, for instance, called Li-Fraumeni syndrome, where people are born with mutant p53 in all their cells. Affected individuals are extremely vulnerable to cancer, tending to develop tumours – perhaps even in babyhood – and often several different types of cancer across their lives. (Among the rest of us, the proportion of patients who develop more than one of the 200-plus types of cancer is vanishingly small.)

Being inherited rather than acquired, Li-Fraumeni syndrome runs in families, explains Rosalind Eeles, who has a specialist clinic at the Royal Marsden hospital in London for people with the syndrome. “But because the cancers are so devastating and they occur at such a young age, the families are generally not very big.”

However, the gene can be disabled by means other than mutation – which helps explain what’s happening in the roughly half of all cancers in which this vital tumour-suppressor appears to be intact. When p53 was first seen in the experiments with the monkey virus, for example, the protein had been trapped and crippled by the virus (though of course nobody realised it at the time). Researchers have discovered, too, that in cervical-cancer cases caused by the human papilloma virus (HPV) – a sexually transmitted infection that can also cause genital warts – p53 is chopped up and devoured by the virus so that the cancer cells have none of the tumour-suppressor at all.

Very recently, Levine’s laboratory at Princeton uncovered a mechanism that explains why healthy p53 cannot prevent breast cancer developing in some cases. Researchers had already found that because it’s such a powerful gene, able to kill or arrest cells, p53 is kept under tight control by another gene called mdm2 that switches it on and off. “It’s like a policeman and his guard dog,” explains one scientist of the relationship between mdm2 and p53. “The policeman decides when to let the dog off the leash to fight a threat, and when to pull it in. If the policeman loses his grip, the dog can cause havoc.” So too with p53: “Mdm2 is what stops p53 killing all our cells – killing us!”

Now Levine and his colleagues discovered that in some people the mdm2 gene is more active than in others, holding p53 on a tighter leash and thus heightening the risk of developing cancer. “What surprised us,” says Levine of the breast-cancer study, “was that this [variant of mdm2] has its largest effect in pre-menopausal women, who have high levels of oestrogen.” So the “policeman” is influenced by the hormone, which amplifies its curbing effect on p53.

Having an overactive version of mdm2 is also bad news for smokers, says Levine. “Tobacco is a stress signal, a carcinogen in the lungs, and smoking alone might double or treble the risk for lung cancer. But two studies make it quite clear that, if you have this genetic risk factor plus tobacco, you have a tenfold increase in the odds of developing cancer.” Lung cancer is the most common cause of death in the UK, with one person newly diagnosed every 15 minutes, according to Action on Smoking and Health. For decades the tobacco industry sought to undermine the case against smoking by claiming that evidence of a link between tobacco and lung cancer, first mooted in the 1950s, was purely circumstantial – there was no physical proof that smoking caused the disease. But p53 has finally nailed the case against tobacco. Since the early 1990s, the International Agency for Research on Cancer (IARC) in Lyons, France, has kept a database of the mutations found in p53 in different tumour types. In the lung cancer of smokers, p53 is overwhelmingly mutated at a particular “hot spot” on the gene. In other words, the gene carries the fingerprint of the cancer-causing agent. Scientists found benzo(a)pyrene, a component of tobacco smoke, is the culprit.


The first paper pinning it down was published in 1996, followed closely by another presenting the evidence from the database. But Big Tobacco had been waiting in the wings. When the papers appeared, it launched an attack questioning the science and challenging the scientists via learned journals. “We’re used to trust within the scientific community, and you expect people to be fair,” says Pierre Hainaut of the IARC. “So the first reaction when you see a paper attacking your work is: ‘Oh my God, I’ve missed something important; I’ve made a big mistake!’”

But when he set out to answer his critics, Hainaut discovered a network of scientists and journal editors not only being paid by the tobacco industry to do their own research on p53, but colluding with the industry to hide the source of their funding and frustrate the scientific debate. They used their contacts to alert tobacco companies to forthcoming publications and helped to prepare papers challenging the data and get them into print as quickly and prominently as possible.

Hainaut followed the trail to secretive institutes set up by the tobacco industry, into the boardrooms of key journals and even the labs of some eminent scientists, and he was shocked. “It may seem very naive, but I had no idea something like this could happen,” he says. “It was like falling into a detective story.”

However, the battle, which turned nasty and personal at times and is well documented in a Lancet article of 2005, did have some positive spin-offs. The rules about declaring conflicts of interest when publishing scientific papers have been tightened. And Hainaut and his colleagues acknowledged the weakness of some data they used to make their original case, and started again from scratch to generate watertight data on the effect of tobacco on p53. Their paper was published in 2005.

Tobacco isn’t the only cancer-causing agent to leave a fingerprint on p53. Many cases of skin cancer have p53 mutations characteristic of ultraviolet radiation from sunlight. And most liver cancers in tropical countries are caused by aflatoxin, a poison secreted by a fungus that infects grains and peanuts, and leave a clear fingerprint on p53.

“Liver cancer is absolutely impossible to treat when it reaches a late stage, so the challenge is to have early detection,” says Hainaut. “The liver releases DNA into the bloodstream, and we can identify the presence of the mutation in it.

Two recent papers demonstrate that we have a very, very strong correlation between the presence of the mutation and cancer. “The feasibility of screening for liver cancer in high-prevalence tropical countries is currently being tested by the IARC and the UK Medical Research Council in west Africa.

Similar studies are under way in the US to see if screening heavy smokers with chronic bronchitis and other “cancer-predisposing symptoms” for mutant p53 in blood or spit samples could be used to identify people likely to develop cancer or to detect early tumours. And Levine believes screening younger women for the higher-acting version of mdm2 that stops p53 working properly might be used to single out those at risk from breast cancer who would benefit from regular mammograms well before their fifties. At the Royal Marsden, Eeles awaits new guidelines from the National Institute for Clinical Excellence (Nice) any day now “that will suggest breast-screening for women under 30 if they have the inherited p53 mutation”.

Though not many places are doing so yet, Hainaut believes the potential to use p53 for the detection and management of cancer is “huge and very important”. P53 research promises novel ways of treating cancer too. Several drugs currently being developed and tested make a virtue of the way viruses invade cells and take over the machinery for their own purposes. In one approach, a common-cold virus, genetically engineered so it cannot cause harm, is used to carry good copies of p53 into cancer cells where it is mutant and useless, thereby reactivating the stress-response machinery. In another, a the virus is engineered so it can infect only cells with dysfunctional p53 – cancer cells – where it grows and multiplies until the cells literally burst.

Besides gene therapy, researchers are looking for small molecules that can be used as tiny tools to tinker with the stress response at various points upstream or downstream of p53. Chemical compounds called “nutlins”, for example – developed by the pharmaceutical giant Hoffman-La Roche, and which interfere with the interaction between p53 and mdm2 – are causing a lot of excitement. Finding a molecule that would “cut the leash between the policeman and his dog”, enabling scientists to switch p53 on and off at will, has become a holy grail.

“I’m very excited about the results with nutlin,” says Lane, who set up a biotech company in the late 1990s to search for such a molecule. “It works very well in tissue culture and animal models, and appears to have good activity in the half of tumours where p53 is not mutant.” That is the case in most leukaemias, half of colon cancer, two-thirds of breast cancer, half of prostate cancer, “so very big numbers”.

Lane stresses, however, that nutlin is still a long way from the marketplace. “It’s not sufficiently drug-like yet to be in clinical trials. But what we call ‘target validation’ – that is, being certain that if we get a drug like this, it will work – is looking very good.”

Drugs to manipulate the p53 system to protect against cancer and slow down ageing at the same time are even further over the horizon, but scientists working to understand this relationship are making some sensational discoveries. Judith Campisi, a p53 and age researcher from Berkeley, California, studies a process called cell senescence. This means cells that lose the ability to divide but remain alive and active, which is one of the options that p53 can choose in responding to stress. “Inability to divide is good news if it means a damaged cell can’t form a tumour,” says Campisi. “But as these non-dividing cells accumulate over time, it’s not such good news, because we’ve seen they’re dysfunctional.”

During normal metabolism, senescent cells produce large amounts of waste material that seep from the cell and begins “to chew up the extra-cellular matrix – the stuff that keeps cells glued together”, explains Campisi. “The major extra-cellular molecule that keeps your skin looking young is collagen. Sure enough, senescent cells produce molecules that destroy collagen.” Hence, wrinkles.

Another theory about how tumour suppression might drive ageing is that, over time, we may simply run out of the stem cells we need to replenish our tissues and organs, as the cells are killed off or stopped from dividing by the stress-response mechanism. “The simplest model would be that you’re born with a limited number of stem cells,” explains Lane. “Those cells are very easily killed off by DNA damage, so they’re the ones most tightly controlled by p53. If you set a [stress-response] threshold where they’re too easily killed, you don’t get cancer but you run out of stem cells more quickly. If you set the threshold where they’re hard to kill, you could live a long time but you’re likely to get cancer.”

With compounds such as nutlins, scientists can manipulate p53 in ways that were once impossible – and for all kinds of therapeutic effects, says Lane, whose belief in the promise of the gene he discovered 27 years ago remains undiminished. “I think one can imagine really quite extraordinary results in the next few years as we begin to be able to control this system,” he says.

Even the idea of resetting our bodies’ stress response to suppress both cancer and ageing does not seem wacky to Lane. But the stakes are high: get the balance right and we will be on the way to longer and healthier lives; get it wrong and we could expire fast and messily in an orgy of apoptosis, as p53, like a guard dog out of control, runs riot in every cell of our bodies.

LIVING WITH CANCER

Natasha Dean has a rare inherited condition that leaves her highly susceptible to cancer. But she is determined to lead a normal life

Natasha Dean’s mother had her first mastectomy at the age of 15, following breast cancer. She had her other breast removed at 19, when cancer recurred, and died from secondaries in the bones at 39, when her daughter was 11. “I was always told by my father and my aunts that I should be careful,” she says. “So I was vigilant from an early age.”

She was on holiday in Australia in 2000 when she went for a routine checkup and discovered a lump in her breast. She was 24. After surgery, chemo- and radiotherapy, she returned to England, where she was referred to the cancer-genetics clinic of the Royal Marsden, London, for a p53 test. “The specialists in Sydney told me I fitted three of the five criteria that would classify someone as having Li-Fraumeni [syndrome],” says Dean. The Royal Marsden confirmed the diagnosis. She and her boyfriend looked it up on the internet, “but it was all quite scary, so I stopped,”she says.“They were very supportive at the hospital and made sure we were aware of the implications. Apparently, there are patients who don’t cope with it very well.” Dean has done so by carrying on with her everyday life.

In January 2004, a routine scan picked up secondary tumours in her liver. She asked to postpone chemotherapy for a few weeks while she married her boyfriend and visited her family in Australia. Treatment with Herceptin and tamoxifen while she was away kept cancer at bay. “The tumours shrank right down till you couldn’t see them any more,” she says. “But after 18 months they started to pop back up. So I had another four cycles of chemotherapy.” With each cycle she returned to her job with an investment bank for two weeks out of three. “Being able to work made it a lot easier getting through it,” she says.

Recently Dean has undergone radio-ablation, a new treatment that involves burning the cancer cells away with radio waves delivered through fine needles directly into the tumour. She is now recovering from a repeat of the procedure after new growth appeared at the edge of the scar.

The mutation in p53 can occur spontaneously in a sperm or egg at any point in a family’s history. Dean believes it began with her grandparents. She and her mother, both only children, are so far the only people affected. “My maternal grandmother passed away at 80, with no cancer. Her mother, my great-grandmother, had breast cancer, but post-menopausal.”

Dean knows she could pass the Li-Fraumeni on to her children. She and her husband have discussed their options with the oncologists. “Until I got the recurrence it was nice to know those options were there. But that’s not something I’m thinking about now,” she says.

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