DNA Disorder Team Blaze a Trail for Cancer Research

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The MRC Cell Mutation Unit has been winning worldwide recognition recently for its pioneering research into forms of rare cancer-prone diseases. Professor Alan Lehmann and his team hosted a workshop on DNA repair disorders last month which was attended by thirty leading international experts. The object of the EU-funded workshop was to examine DNA disorders which lead to skin cancer and other life-threatening conditions such as leukaemia and immuno-deficiency problems.

Alan's own research scrutinises the effects of rogue DNA to uncover the secrets of these genetic disorders. And the team has just won another in a long line of lucrative grants - from the Association for International Cancer Research - to pursue its trailblazing project. The charity's chief executive, David Napier, hailed Alan's work as "among the cream of the crop in scientific research into cancer."

Alan's research is centred on the disorder xeroderma pigmentosum - or XP - which causes severe and extensive skin cancer on exposure to sunlight. Although the disorder is rare - there are about 100 XP sufferers in the UK, and the incidence is about 1:250,000 worldwide - it can be fatal. As Alan points out - "If you have XP and you go out unprotected even on a cloudy day you will end up with skin cancer. You can protect yourself with barrier creams and protective clothing, but it is better not to go out in daylight at all."

People with XP have a defective gene which means they can't regenerate cells that become damaged by ultraviolet light. As Alan explains, "When anyone goes out in the sun, DNA in their skin cells becomes damaged immediately. But most of us have a battery of systems to repair all types of damage.

"For most of us, the damaged section of DNA is repaired by proteins, which act as the 'workmen' of the cell. The DNA buckles when it is damaged, and the 'workmen' cut out and replace the buckled section with healthy DNA. Most of us do this efficiently - it is a process which from recognition to replace -ment only takes around two minutes. But people with XP can't because they are missing one of the 'workmen' - a protein which is vital to the process." In fact, XP sufferers could be missing any one, or more, of ten proteins which govern the recognition, removal and replacement of damaged DNA.

Crucially, Alan's research has led him to uncover links between XP and other inherited disorders which have radically different symptoms. The disease trichothiodystrophy (TTD), which causes scaly skin and brittle, sulphur-deficient hair together with mental and physical retardation, has also been found to be caused by the inability of cells to repair their DNA. Because they are so rare, and the symptoms so generic, such diseases are very difficult to diagnose.

In fact, it is the common tendency to misdiagnose these conditions and treat them inappropriately which puts the work of Alan and his team at a premium. Although these disorders are incurable, early treatment can mean the difference between life and death. The Sussex team make around thirty diagnoses a year by examining the cell tissues of patients sent to them by doctors from around the world.

By using cells from these patients, Alan can understand at 'gene level' what is causing the disorders. He grows cell cultures which have defective DNA repair, and beams UV light on the cells to investigate what happens. He then compares this process with the effect UV light has on healthy skin cell cultures. "Donating a piece of skin is the price of setting foot in this building," he jokes.

"From our work we are able to understand what causes these disorders, but we are also able to understand more about skin cancer in general. And by looking at the way these disorders relate to each other, we can learn more about the way DNA works in all of our bodies. This mysterious process is something all scientists would love to know more about," says Alan.