SCIENCE / The ills of the children: As the first UK trial of gene therapy is approved, Steve Connor begins a three-part series by looking at how scientists hunt the genes responsible for inherited diseases

THE GLOBIN GENE

'This gene is in many ways a paradigm for the field as a whole,' says Frank Grosveld, a senior scientist at the National Institute of

Medical Research near London. It was one of the first human genes to be 'cloned' by inserting it into microbes and is probably the most studied bit of DNA.

It carries the instructions for the manufacture of the globin protein, used in haemoglobin, the oxygen-carrying substance of red blood cells. Defects in the globin gene - and more than 100 have been identified - can result in blood disorders such as sickle-cell anaemia. There are about 240 million carriers of mutations in the globin gene, many of whom are living in the developing world where the mutations can give some resistance against malaria.

CYSTIC FIBROSIS GENE

Cystic fibrosis, which is marked by a build-up of sticky mucus in the lungs, is the most common genetic disease in people of north European stock, with about one in 20 being a healthy carrier of the defective gene. Discovery of the gene quickly led to a better understanding of the disease, the development of a reliable test for defective genes and the possibility of gene therapy.

Children who are suffering from cystic fibrosis have inherited two defective copies of the gene, one from each parent. The gene is responsible for the production of a protein that transports salt (more specifically chloride ions) between cells that line the lungs, intestines and other organs. Defects in the gene disrupt the mechanism and result in the severe symptoms of the disease.

HUNTINGTON'S CHOREA GENE

The final isolation of this gene has escaped the strenous efforts of researchers, who are hampered by the density of genes in this particular region of the human genome. However, nearby genetic markers can be used to identify carriers with about 97 per cent certainty. Sufferers from the disease have inherited just one copy of the defective gene from one parent - it is therefore a dominant gene. Carriers lead quite normal lives until they approach middle age, when the first symptoms of neuro-degeneration appear. The delayed onset of the fatal symptoms of this condition makes it particularly distressing for sufferers and their families.

G6PD - 'HOUSEKEEPING GENE'

This gene is present and working in every cell of the body, and is vital for day-to-day

'housekeeping' functions necessary for energy metabolism. The gene is responsible for the production of a vital enzyme, called glucose 6-phosphate dehydrogenase (G6PD). Scientists from the Royal Postgraduate Medical School in London helped to identify the gene in 1986. About 400 million people in the world carry defects in the gene. Most mutations, however, have little or no effect, although some can cause acute haemolytic anaemia, destroying blood cells.

BREAST CANCER GENE

Scientists are very close to identifying a gene responsible for giving some women a predisposition to breast cancer. About a dozen research groups working on some 250 families with a history of breast cancer have pooled resources to home in on a stretch of DNA on chromosome number 17. The gene itself could be found within a year.

Other types of tumours also have strong genetic components and scientists are confident that they will be able to identify the genes involved. Heart disease and high blood pressure are also on the list of major killers that involve the inheritance of a number of predisposition genes.