Researchers ID Gene Tied to Some Cases of `Bubble Boy' Disease

10-year hunt through the DNA of humans and fruit flies has led researchers to a gene that causes some cases of ``bubble boy disease,'' in which the body can't protect itself from even the most common germs.

Severe combined immunodeficiency disease, or SCID, is a rare inherited disorder that deprives children of healthy immune systems, making then susceptible to potentially fatal infections. The defective gene, identified by researchers at Harvard Medical School, keeps calcium from activating infection- fighting white blood cells.

The discovery means the next time a child is diagnosed with SCID, doctors may genetically screen him or her to look for this new culprit gene, then replace it using a technique that may allow the patient to develop their own immune system.

``Every time you can identify the genetic cause of a disease, it opens up new opportunities to try to treat it,'' said Michael Blaese, medical director of the Immune Deficiency Foundation in Towson Maryland, in a telephone interview Friday. Blaese wasn't involved in the research.

The condition affects about one in every 500,000 births. Children with it begin developing viral, bacterial or fungal infections as early as three months of age, and are unable to fight them. The disorder is called ``Bubble Boy Disease'' because patients are often protected from infection in special rooms or plastic bubbles with controlled environments.

Hunt Begins

Several genes have already been tied to different forms of SCID. The hunt for this particular gene began in 1993 after a child was brought into an immunodeficiency clinic in Germany with a viral infection and raging fever. He died at 11 months. A brother born two years later had the same symptoms. He survived after getting a bone marrow transplant.

A young doctor named Stefan Feske was doing a medical internship at the clinic. When he later got a job in the laboratory of Anjana Roa, a senior investigator at the CBR Institute for Biomedical Research at Harvard Medical School, he brought the boys' cell lines with him. The two scientists were among the authors of a paper on the new gene published in the science journal Nature.

The researchers began searching for a cause of the boys' immune deficiency and found that calcium wasn't entering their immune cells. They believed this was likely caused by a single gene mutation because the boy's parents were first cousins and their grandparents were siblings.

They then searched for the gene using two methods.

One involved following genetic signposts, called single nucleotide polymorphisms, to identify regions in the genome that might be linked to the disorder. That helped narrow the field.

Sophisticated Technique

They then turned to a more sophisticated technique, systematically engineering mutations that blocked the action of genes in fruit fly cells until they found one that made the cells behave like those seen in the boys.

``That's the beauty of evolution,'' said Rao, the lead author of the paper, in an interview Friday. ``It has preserved the pathways that extend from fruit flies all the way to humans.''

Children with SCID can usually be cured if they get a bone marrow transplant from a matched donor, usually a sibling. Unfortunately, matched donors are not available for most children with this condition.

If the gene causing their condition is among several that have been identified to date, these children too can sometimes be helped with gene therapy techniques. Rao's discovery pinpoints an additional gene and could lead to a treatment.

Gene Therapy

Doctors could remove some of a patient's bone marrow, inject a normal version of the defective gene into the stem cells found there, and allow them to grow in a dish. They could then put the stem cells back into the bone marrow of the patient, where they could grow normal blood cells capable of fighting infections.

This type of therapy has helped a number of children though it also carries some risks. In some cases, the method doctors use to insert a corrected gene into the patient have altered other genes, causing leukemia.

``Gene therapy has proven itself to be an effective form of treatment for SCID,'' said Blaese, who performed the first gene therapy procedure on a child with a different form of SCID 15 years ago. ''It would lead you to think you'd have a pretty good chance.''