One infant in every hundred is born with a serious genetic disease or condition. Usually the problem becomes obvious to parents and children quite early in a child's life. All too often, the disease results in physical or mental disabilities, prolonged and severe pain, and a shortened life. More than 4,000 inherited disorders are known. But until now, most have lacked fully effective treatments.

 

It is no wonder, then, that scientists have long imagined being able to treat or even cure inherited diseases by replacing the disease-causing genes in a patient's body with healthy ones. Today, these exciting developments are just beginning to take place. In the future, they will become increasingly important.

 

Scientists are tracking down more and more of the genes responsible for the various inherited disorders that afflict human beings. A new and important field of medicine, known as GENE THERAPY, is opening up.

 

Targets for Therapy

Among the commonest of genetic disorders is Down syndrome. Children born with Down syndrome are mentally disabled. The cause of their condition is that their bdy cells contain 47 chromosomes instead of the usual 46.

 

Most inherited conditions, however, do not result from problems with whole chromosomes but with tiny parts of them. In fact, a number of common genetic diseases are caused by just one faulty gene. It is these single-gene disorders, such as cystic fibrosis and hemophilia, that promise to be the simplest to treat by gene therapy.

 

Another condition caused by a single disease-causing gene is known as severe combined immunodeficiency, or SCID. Children with SCID do not have enough white blood cells. These cells are produced in the BONE MARROW and are one of the body's main lines of defense. White blood cells recognize and destroy foreign particles, such as bacteria, that invade the bloodstream. People who don't have an adequate supply of white blood cells cannot fight infections.

 

In about a quarter of all SCID cases, the problem lies with a gene that carries the code for making a protein called ADA. It this gene is faulty or missing, all of the cells in a person's body are slightly damaged because they cannot manufacture the ADA they need. The most seriously affected cells, however, are in the bone marrow. Without ADA, a person's bone marrow cells cannot make healthy white blood cells.

 

The DA gene was among the first to be linked to a particular genetic disorder. In 1990, at the National Institutes of Health in Bethseda, Maryland, the ADA gene became the target of the world's first trial of gene therapy on a human being. The patient was a four-year old girl.

 

New Genes for Old

One way that doctors can carry out gene therapy is by using viruses. Normally, viruses cause disease. They do this by attacking cells in the body and inserting their own genes into the DNA of the cells (see Figure 2). The infected body cell now has instructions to make more copies of the virus. Eventually, these copies burst out, killing the infected cell. Then they go on to attack other cells.

 

Specially alter viruses, however, can be valuable because they provide a means of delivering healthy genes into a patient's body cells. The first step in preparing a virus for use in gene therapy is to make it safe. This involves changing the virus so that it cannot be reproduced and so destroy the cells it enters. The second step is to add to the virus a healthy gene. This is the method currently being used in the gene therapy for SCID.

 

Doctors add a healthy ADA gene, taken from a normal human cell, to a special kind of virus called a RETROVIRUS. Retroviruses are used in gene therapy because they have a very simple genetic structure and are, therefore, easy to work with. The altered retrovirus is added to a sample of STEM CELLS taken from the bone marrow of a child suffering from SCID. Stem cells are the cells from which white blood cells develop.

 

Each retrovirus fixes itself to a stem cell and releases its genes into the cell. The healthy ADA gene from the retrovirus becomes "stitched" in to the DNA inside the cell's nucleus so that the stem cell can now make normal amounts of ADA.

 

When the large numbers of stem cells in the sample taken from the patient have been changed by the virus, they are injected back into the patient's bone marrow. Because they now produce their own ADA, the stem cells can develop into white blood cells as they would in a healthy person. One treatment results in enough white blood cells to help the patient fight off infections for two to three months. Then the process has to be repeated.

 

Future Progress in Gene Therapy

Taking living cells from a patient, replacing disease-causing genes, and then putting the altered cells back into the patient's body is called AUGMENTATION THERAPY. This is likely to be the commonest form of gene therapy for a number of years to come. However, it cannot provide a permanent cure for genetic disease because too many of the patient's cells remain untreated.

 

Lasting cures for genetic disease will involve more advanced forms of gene therapy. Ideally, doctors would like to be able to take out the faulty genes from every cell in all or part of a patient's body and put healthy genes in their place. No one yet knows how to do this successfully. In the future, researchers may find a way to deliver replacement genes to many millions of different cells inside the human body. Special chemicals or viruses, for example, could be used to deliver the genes to the right places in the body.

 

Simply getting a healthy gene into a cell, however, is not the end of the problem. A gene will work only if its coded instructions are read by the cell. This can happen only if the bits of DNA on either side of the gene, which are like punctuation marks (called "codons"), are properly positioned and undamaged. Another problem is that a new gene that finds its way into the wrong part of a chromosome could act as a trigger for cancer. In time, these complications may be overcome. Meanwhile, doctors and lawmakers are trying to come to grips with some of the difficult ethical questions raised by gene therapy.

 

Rules to Live By

Gene therapy is so new that no one can really be sure what long-term effects it might have. Experiments conducted on animals have shown that changes to faulty genes can sometimes be carried out safely and successfully. However, when an error is made, it can lead to a further genetic disease in the animal and its offspring. Because of this, some specialists argue that gene therapy has not been tested fully enough for these experiments to be continued n human beings.

 

So far, gene therapy trials on children with SCID have involved making changes to ordinary body cells, not to reproductive cells. The Altered ADA gene is not able to leave the white blood cells and find its way into the DNA in egg and sperm cells. This distinction is very important. Many doctors think it is acceptable to replace a disease-causing gene in a single individual. But because the long-term effects of gene therapy are still unknown, opinion is divided about making genetic changes that would be passed on to future generations.

 

Setbacks and Surprises

Recently, it has become clear that even single-gene diseases may prove much harder to treat than was originally expected. The gene that causes cystic fibrosis, for instance, has been found to come in hundreds of slightly different forms, called MUTATIONS.

 

With so many possible mutations, the number of combinations in a person who inherits one CF gene from each parent is almost endless. Researchers are finding that pairings of different mutations produce different effects. Some pairings may cause severe cystic fibrosis, while others lead to less serious disorders like asthma or bronchitis. It also seems that other genes could affect the way different mutations of the CF gene behave. For instance, a pair of mutations inherited by one person might behave differently from the same pair inherited by another person, depending on the state of a third, controlling gene.

 

These discoveries make the task of genetic counselling much more difficult. Counseling can still be expected to make reliable predictions in the case of a family that has a known history of CF. But doctors now believe it may be much riskier to offer opinions about individuals who have no family history of the disease or who have inherited a pair of mutations that scientists are still unfamiliar with.

 

NEXT PAGE  •  PREVIOUS PAGE  •  CONTENTS