One gene, two functions, three diseases

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"Curing cancer is one of the major challenges of the current millennium," says Professor Alan Lehmann. "And you can only hope to cure cancer if you understand how it is generated in the first place."

The ultimate goal of a cure is still a long way off. But the progress made by Alan and his scientific colleagues in an international research consortium was recognised at a ceremony in Brussels last week, when they received one of three René Descartes prizes awarded by the European Commission.

More than 100 networks of teams competed for the prize, worth about £40,000 to each of the winning laboratories.

Making the presentation to Alan, Research Commissioner Philippe Busquin said: "This new prize recognises successful cross-border teamwork and European networking, which is often a determining factor of outstanding quality of science."

Promoting trans-national research co-operation is not a new idea in Europe and the European Union (EU) has been funding such partnerships for 15 years. Alan's team at the MRC Cell Mutation Unit currently has EU funding for three collaborative projects, of which the prize-winning study is one.

Over the past decade, the Sussex team and their colleagues in Italy, the Netherlands and France have been looking at a number of diseases in which a faulty gene means that the body is unable to repair damage to its DNA, or genetic material.

Their work involves beaming ultraviolet light on to abnormal skin cells - as well as a control sample of normal cells - and then analysing the DNA for damage.

The prizewinning consortium has focused in particular on just one gene, called XPD, which demonstrates unusual characteristics. In most cases, a defect in a gene can result in only one genetic disorder. The researchers made the remarkable discovery, however, that not one but three conditions can result from a faulty XPD gene.

In some cases, it can cause xeroderma pigmentosum (XP), which gives sufferers a hugely increased chance of developing skin cancer. In other cases, the faulty gene is linked to two quite different diseases, trichothiodystrophy (TTD) or Cockayne Syndrome.

"This discovery was very surprising, because the diseases are completely different," says Alan. "It's a bit like finding that a fault in your fuse box can wreck not only your electric supply but also the water supply."

The breakthrough in explaining how a single gene could cause three different disorders came with another surprise discovery: that the XPD protein - the molecule that does all the work in the cell - has not one function, as is the case with most proteins, but two.

It is needed to repair damage in the DNA caused by sunlight, but is also used in the quite different process of transcription, the mechanism with which the cell reads genetic information and converts it into proteins.

"Nobody had expected this," recalls Alan. "It was a staggering discovery and everybody was quite astonished. But once it was made, it immediately provided a lot of possible explanations."

The researchers suggested that if the fault in the XPD gene affects DNA repair, the patient has XP; but if it alters transcription, TTD or Cockayne Syndrome will develop. In their next series of experiments, they were able to show that this was indeed the case.

Armed with this knowledge, Alan and his Sussex team can now help doctors around the world in diagnosing patients by examining their cell tissue.

Early diagnosis of XP - at birth or even in the womb - means that parents can make sure their child wears protective clothing and keeps out of the sun. "If you look at children who have been well protected from birth, you can barely tell they've got XP," says Alan.

The three diseases can only be cured, however, if scientists can work out how to replace the defective XPD gene - and Alan estimates that this breakthrough is at least another five or 10 years away.