Gene therapy: simple in theory but difficult in practice

This essay was written by Peter Rigby and was first published in the 1995 Mill Hill Essays.

Every year a considerable number of children are born with a genetic disease, a disease that occurs because each of their parents carries a defect in the same gene. The cells that carry the genetic information from one generation to the next, the egg in the female and the sperm in the male, are the only cells in the body which contain only one copy of the information. When they fuse together, the fertilised egg from which the whole body develops now contains two copies of the information. So if a gene in the copy from one of the parents is faulty the gene in the copy from the other is able to compensate and the child can still develop normally. However, if the fertilised egg is formed with two faulty copies of the same gene, one from each parent, the child may be born with a major clinical problem or it may die during the pregnancy. The commonest disease of this sort in the UK, with about three hundred affected children born each year, is cystic fibrosis, which leads to a clogging of the lungs, and to problems with digestion and other functions. Although improvements in care and treatment mean that people with cystic fibrosis can now live for up to twenty-five years, there is no cure. A much rarer but nevertheless well known disease, is severe combined immunodeficiency. SCID children with this condition have a defect in both copies of a gene which is required for the proper functioning of the immune system, which protects us against infectious diseases. The children can be kept alive but they have to live in sterile plastic bubbles to isolate them from bacteria and viruses which, while they may make the rest of us ill, are kept under control by our immune systems. These children would die of infections which would only keep the rest of us in bed for a couple of days. Again, while there are treatments, there is no cure.

However, in simple terms the cure is obvious. If the children are ill because they have two bad copies of a gene, it follows that if we could give them a good copy of the gene they would then be like their parents and be healthy. This very obvious idea is called gene therapy. While the idea is obvious, the way in which the gene might be put into the relevant cells of the child is not at all clear and there are also many issues concerned with safety, economics and ethics, which mean that progress on gene therapy has been rather slow.

To do gene therapy means to change the genetic constitution of a human being and this has raised concerns in society at large. If we can change somebody’s genes in order to cure cystic fibrosis then, it is argued, we could change their genes to make them taller, or cleverer, or to give them blond hair. These things are not possible because we do not know about genes for intelligence, or height but the issue of principle remains. The question of whether gene therapy is or is not ethical has therefore been widely discussed. In many countries governments set up committees which included not only scientists and doctors but also religious leaders, lawyers and ethicists, to consider the matter. In all cases the conclusion was that gene therapy did not pose any new ethical dilemmas so long as it was used to relieve clinical symptoms, and being short or having brown hair would not be regarded as a clinical symptom. The committees also drew one crucially important distinction. As we shall see, all of the current approaches to gene therapy seek to introduce the good gene into the so-called somatic cells of a child or an adult. Somatic cells are those which make up the vast majority of our bodies. They include every type of cell except the germ cells which give rise to eggs in females and sperm in males. So any changes which are made to the genetic constitution of a somatic cell are not passed on to a person’s offspring. While somatic gene therapy is thought to be appropriate, germ line gene therapy, in which the changes would be made in germ cells and so would be passed on to the offspring, is not allowed.

If we wished to use gene therapy to treat someone with an inherited genetic disease, how might we go about it? We need firstly a fairly detailed understanding of the disease; why it is that the lack of a particular gene product causes the symptoms, and we need to know in which cells of the body the gene is required. We will take the immunodeficiency disease described previously as an example because it is fairly straightforward. Although the gene is active in all the cells of the body, the children only have problems with their immune systems; either the gene is not needed in other cells or another one can substitute for it. So we only have to get an undamaged copy of the gene into the cells of the immune system, which are in our blood, that make antibodies and kill virus-infected cells. That makes things easier because it is very simple to inject things into blood, or to take blood cells out of a patient, do something to them, and put them back, as is done in blood transfusion centres every day. But we can not simply inject the gene into the bloodstream. Genes are made of DNA, which is quite a fragile chemical, and if one simply injected it into blood it would be destroyed. So we have to construct some kind of carrier, called a vector, that we can use to transfer the good gene into the patient’s cells. Fortunately nature has provided us with highly efficient vectors in the form of viruses. Viruses are parasites which can multiply only inside the cells of living organisms and they have therefore evolved extremely efficient ways of inserting their own genes into the cells of the host that they infect. Much of gene therapy research thus far has involved modifying viruses so that instead of introducing their own genes they introduce a therapeutic gene which will cure the patient’s disease.

The viruses that have been most commonly used are called retroviruses which, unlike most viruses, do not kill the cells that they infect. Gene therapy vectors are made from viruses that normally infect mice. They are turned into vectors by first removing the genes that the virus needs to carry with it to enable it to replicate inside the cells it infects. The genes removed are then replaced in the virus by a perfect copy of the gene which is missing or damaged in the patient. The other vital component is a special cell that has been adapted to make the proteins that the virus needs for its coat and its replication. When the vector is put into one of these special packaging cells, the therapeutic gene is wrapped up in the virus’ coat and expelled from the cell as a particle which from the outside can not be distinguished from the parent virus. The fact that the genes required for virus replication have been removed means that the genetically modified virus can only deliver the therapeutic gene to the first cell that it enters. It can not start an infection and this removes any risk of unwanted side effects.

The vector can now be used to transfer the gene into a patient. This can be done in one of two ways. In most gene therapy that has been done so far, cells are taken out of the patient and then, in the laboratory, are infected with the virus. Once the researchers know that the infection has been successful, the cells can be infused back into the patient where, all being well, the therapeutic gene will be active and the genetic defect will be overcome. In the other type of gene therapy the vector is put directly into the patient. This is much more difficult because the patient’s body senses the incoming vector as foreign and thus likely to be dangerous. The immune system will therefore try to destroy it and the immunological responses mounted by the body can be just as bad for the patient as a severe viral infection. Moreover, if we inject the vector into the bloodstream we can not control where it goes and so it is possible that the therapeutic gene will end up in the wrong cells.

There have been a number of trials of the first type of gene therapy for severe combined immunodeficiency and we can say that the treatment does not do the patients any harm; if all of the checks and tests are done properly, it is safe. It also seems that, in some cases at least, the patients improve, but a great deal of work still has to be done before we can be sure of that.

Although the initial definition of gene therapy dealt exclusively with the idea of treating people with an inherited genetic disease, most of the research in the field today is concerned with the treatment of cancer. It has long been thought that when a cell in the body becomes cancerous it activates genes that it ought not to and should be recognised by the body’s immune system as if it were foreign. If that were so, and the immune system worked properly, then none of us would get cancer, so things clearly do not work quite like that. A very popular idea at present is that the cells of our immune system can recognise the cancerous cell as foreign but that for some reason they do not do what they are supposed to do and kill it. In most cases gene therapy for cancer involves transferring genes which are thought likely to improve the immunological response to the cancer into either the cancerous cells themselves or the cells of the patient’s immune system. In experiments with laboratory animals that have tumours these approaches are spectacularly successful, the tumours are completely cured. There are now a number of clinical trials in which researchers around the world are trying to find out if the same things happen in humans who have incurable cancers.

While the underlying principle of gene therapy is not particularly complicated, it has become clear in the past few years that the practice is anything but simple. The major problem is in designing vectors which are efficient and safe, and which can be injected into the body. The vectors that we have available today either provoke immune responses in the patient, or are inactivated by components of human blood, or are very inefficient, or have some other problem. Moreover, it has proved to be very difficult to arrange for the therapeutic gene to continue to work for long periods of time, and we do not know how to target the vector accurately to the cells that we want to treat.

It is quite clear that if gene therapy is to become a standard way of treating people then there will have to be dramatic improvements in vector design. Indeed it seems likely that the vectors of the future will not be any of the systems that we know about; they will probably be hybrids that use individual components from the systems available today. It is also now clear that there has been a little too much enthusiasm about gene therapy. Some people assumed that just because the idea is simple it would work easily. They could not have been more wrong, and in the next few years it will be very important that much effort is put into fundamental work in the laboratory to show that effective gene therapy is possible. Only when that has been done will it be sensible to return to clinical trials.

Even when all of the scientific and clinical problems are solved, it is still not clear that all of the patients who could benefit from gene therapy will get the treatment. All of the materials, the vectors, that are used in gene therapy trials and treatments have to be made under stringent conditions and exhaustively tested to ensure that they are safe. This means that each treatment will be very expensive and that the materials can only be made in special facilities by those who possess special expertise. For many of the genetic diseases the number of patients is so small that it is not economically worthwhile for pharmaceutical companies to commit their resources. However, if gene therapy works for common conditions like cancer, or asthma, or heart disease, then the situation will be quite different; the huge market size will ensure that the problems are overcome.

I think that in the long term gene therapy will become a very important part of the armoury with which we combat disease. We are rapidly learning about the genes which predispose us to the common diseases of the heart, the circulation and the brain, and if gene therapy can be used to counter such predispositions then it will be of enormous importance. However, it is clear that a very great deal of research, in both the laboratory and the clinic, is going to be required before this idea can make a significant impact on our well-being. The curing of important diseases by gene therapy is not just around the corner.

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