Gene therapy - the selective insertion of genes into the patient's body - is a source of great hope, but also of fear
By Uri Nitzan
Photo: Avihai Nitzan - Prof. Amos Fant. The challenge: to introduce the gene
installed through the cell membrane
In the last decade, gene therapy occupied a central place in the vision of medicine
Future. Prof. Amos Fant, from the department of microbiology at the university
Hebrew, devotes a significant part of his time to the developing field.
The goal of gene therapy is to develop the ability to selectively insert genes into the patient's body. In the case of a disease resulting from a lack of expression of a gene, its artificial insertion into the DNA can cure the diseased cells. For example, in the hereditary disease cystic fibrosis (CF) there is a specific defective gene in all the cells of the patient's body. The lack of the gene causes severe symptoms, mainly in the respiratory system, and in most cases the patients die before they turn 30. Inserting the normal gene into the cells, and combining it with the defective DNA, will restore the normal feature they are missing to the patients, and cure them.
In order for a gene to integrate into the DNA of a cell and function properly, it has to penetrate through the cell membrane. This is the main obstacle on the way to the application of gene therapy in humans. To get around the obstacle, the researchers make use of the natural properties of viruses, and insert their genes into the human cell. Therefore, in order to understand the mechanism of gene therapy, and the power inherent in it, one must know the world of viruses.
Each virus consists of a core containing hereditary material - DNA or RNA - and a protein coat. The distinct feature of viruses is that they are parasites (hosts). They lack the ability to replicate themselves and produce proteins, and therefore developed the ability to penetrate the cell of another organism (host) and incorporate their genetic material into its DNA. They multiply with the help of the mechanisms of the host cells, and at some point break through the cell membrane, spread in the blood and infect other cells. The ability of a virus to survive therefore depends on its ability to lodge and enslave the host's cells for its needs.
The cornerstone of gene therapy is the understanding that it is possible to infect diseased cells with a virus carrying a normal gene that they are missing, and cure them. In the first stage of preparing the carrier virus, its genetic material is sterilized from harmful components, and the normal gene is inserted into it. In the second stage, the diseased tissue is infected with the virus that carries it, and its natural ability is used to insert its hereditary material, including the normal gene, into the DNA of the damaged cells. The normal gene integrates into the DNA of the diseased cells, and the protein begins to be expressed.
Prof. Fant began his research career in the early stages of the development of genetics and familiarity with viruses. In the 70s, under the guidance of Nobel laureate Gobind Korna, Fent developed methods for building gardens under laboratory conditions. Later, the two discovered a technique that allows the multiplication of genes in a test tube. This method was perfected ten years later in the laboratories of the "Citus" company and today it is used by researchers in many fields of medicine, and is called
.PCR
In those years, virus research began to gain momentum - culminating in the XNUMXs with the discovery of the AIDS virus - and Fant chose to focus on research in virology. Today Fent and his research group are engaged in the development of two new techniques for gene therapy.
The first technique is based on in vitro research. Fant, in collaboration with Prof. Eduardo Mitrani from the Faculty of Life Sciences at the Hebrew University, removed lung tissue from mice suffering from cystic fibrosis, and under laboratory conditions infected the tissue with a virus carrying the normal gene. after the
The healthy lung tissue was then transplanted under the skin of the mouse (it was not returned to its natural place). After three months, the transplanted tissue was tested, and it was found that it retained all the initial characteristics of the lung, and in addition expressed the gene that was inserted into it outside the body.
In this way Fent also treated mice that suffered from a lack of growth hormone. he
He removed tissue from the mice, and infected it with a virus that contained the normal growth hormone gene. The repaired tissue was then implanted under the skin of the mice. In the tests it was found that the growth hormone is indeed secreted from the cells of the implant, and that it flows in the blood of the mice. The possibility of controlling the release of the growth hormone into the blood will allow treatment of children who lack the gene and grow at a slow rate, and cancer and AIDS patients who suffer from dangerous weight loss.
The second technique is based on intracorporeal research. Fant, in collaboration with Dr. Aharon Plamon from the Faculty of Dentistry, infected the salivary glands of mice with a virus that carried genes of therapeutic value. The virus was introduced into the salivary duct in the oral cavity with the help of a thin tube, and from there it was injected into the salivary gland. Thus, for example, a gene coding for interferon was inserted into the DNA of the gland cells. Interferon is a protein used to treat diseases such as chronic jaundice and multiple sclerosis. In the tests conducted after the gene therapy, it was found that the salivary gland cells began to secrete the interferon protein into the blood of the mice.
The great hope that researchers have in genetic medicine is overshadowed by the fear of new dangers. Theoretically, the introduction of a gene into a vital region of the DNA can harm the cell, and subsequently cause the patient more harm than good. In addition, it is difficult to predict the dose in which the cells will produce the normal protein, and there is uncertainty as to the body's reaction to a virus that carries the normal gene.
To date, the gene therapy method has been tried on about 4,000 patients - in most cases without success. The source of the failures was often a lack of scientific substantiation of the technical procedures in the laboratory, and the researchers running too fast for clinical trials in humans. One of the few successful attempts was made in "bubble children" in France. These children were born with a lack of one of the genes essential to the functioning of the immune system, and were condemned to life in a sterile bubble at best, or to a quick death as a result of infections at worst. The researchers succeeded in correcting the genetic defect in the children's bone marrow cells, thus restoring their immune system and curing them of the disease.
{Appeared in Haaretz newspaper, 18/12/2000{
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