Gene therapy for prolonging life and treating diseases: from worm to human
The worms tried the longevity pill. The person will be next
The latest advances in gene therapy are shockingAlexander Panchin, Novaya Gazeta, 04.05.2010
Modern research suggests that gene therapy has a huge potential: manipulations with genes have already made it possible to extend the life of a number of living organisms several times. Of course, the "longevity pills" that can be "eaten and washed down with water" that have already been found for worms are on the verge of fiction when it comes to prolonging a person's life. Nevertheless, today there is an active search for gene therapy drugs and ways to deliver them to human cells. Success has been achieved in the treatment of a number of diseases.
Man and the roundworm Caenorhabditis elegans are similar organisms. About half of the worm's genes can be found in humans. There is an expression in the Bible, "I am a worm..." (Psalms 21:7), which well illustrates this similarity and is consistent with evolutionary ideas about the relationship of these species. This is of great practical importance – many human genetic diseases also exist in the worm, and it is more convenient to study the worm than a person. A lot of discoveries have been made on the worm, for example, genes have been found, disabling which can prolong the life of this organism by 2.5–10 times. You can selectively disable worm genes by adding special double–stranded RNA molecules to their food (RNA are intermediate molecules that transmit information from genes for protein synthesis). That is, a "longevity pill" has been found for the worm.
Two key elements in the work of such therapy are special channels through which double-stranded RNA is carried throughout the body, and a complex system of RNA interference, a mechanism that directionally suppresses the production of protein encoded by the target gene. Humans also have RNA interference, and there are channels similar to those of a worm, but such a convenient system for delivering information molecules throughout the body has not yet been discovered. Other delivery systems, such as viruses, are used in human gene therapy.
Retroviruses are able to create DNA copies of their genome and embed them into the chromosomes of host cells. The most well-known examples of retroviruses are human immunodeficiency virus (HIV) and hepatitis B virus (others are used for therapy). With the help of genetic engineering, you can remove the part of the retrovirus genome that causes the disease and insert a useful gene. If a gene in a cell is corrupted, and the virus brings a working copy of this gene, we can expect the restoration of the lost function, the recovery of the cell.
Treatment of hereditary immunodeficiency
Lymphocytes play an important role in human immunity. With the normal development of the immune system, the precursors of lymphocytes undergo genetic rearrangements, due to which many populations of lymphocytes arise, each with a unique set of receptors - proteins necessary for the recognition of foreign agents. Since the variety of receptors turns out to be huge, there is a group of lymphocytes capable of recognizing it for almost any infection. When an infection enters the body, the lymphocytes that recognize it begin to actively divide. Interleukins and their receptors play an important role in this. If there is no receptor for interleukins or it is damaged, immune cells practically do not multiply, severe combined immunodeficiency syndrome occurs.
In 1972, a boy, David Vetter, was born in Texas, who was diagnosed with this. The boy became known for having lived in a sterile room for 12 years, in a "bubble". Despite the precautions, the boy died as a result of a severe infection with the Epstein-Barr virus. There was no cure in those days. Today, with the help of genetically modified retroviruses, it is possible to insert the correct copy of the interleukin receptor gene into lymphocytes and correct the defect. Dozens of children have already been cured in this way.
Cancer TreatmentRetroviruses are not the only type of viruses that are used for gene therapy.
Adenoviruses (for example, pathogens of bronchitis, conjunctivitis, colds) do not embed their genome into the host chromosomes. This has one advantage: there is no risk that the viral DNA, being embedded in the chromosome, will accidentally damage some important gene (such inserts can lead to diseases, for example, cancer). Moreover, genetically modified adenoviruses have shown themselves to be on the good side in the fight against cancer.
Cancer occurs when a cell begins to divide uncontrollably, usually as a result of damage to a number of genes. Genetic analysis has shown that very often in cancer cells there is a mutation in the gene that encodes the protein p53. If the cell is severely damaged, the p53 protein can prevent the cell from dividing and even cause it to commit "suicide". That is why in many cases, in order for a cell to become cancerous, the p53 protein gene must deteriorate. In such cases, the introduction of a healthy p53 gene with the help of a virus should stop the development of the tumor. This approach is the basis of the drug gendicin, which has been clinically tested in China. Gendicin contains a genetically modified adenovirus, which is not able to reproduce independently and cause diseases, but contains a working copy of p53.
Another way to fight cancer is to use the immune system. In some cases, cancer cells differ from normal cells by markers (special proteins in their membrane). These markers can be recognized by cells of the immune system – lymphocytes. If a person lacks lymphocytes with suitable receptors, the immune system does not recognize cancer cells and does not fight them. In 2006, the results of the following treatment procedure for melanoma (skin cancer) were published in the prestigious scientific journal Science. Lymphocytes are taken from the patient and placed in a test tube, and then modified with retroviruses: a receptor gene for a cancer marker characteristic of melanoma is inserted into them. Lymphocytes are launched back into the patient's blood. The use of this procedure led to regression of metastatic melanoma in several patients: an immune response appeared to melanoma cells.
The causative agent of pseudotuberculosis, a relative of the plague, has a gene that allows bacteria to penetrate into human cells as part of membrane vesicles. The causative agent of listeriosis has a gene responsible for the destruction of membrane vesicles and the release of the contents of the bacterium into the cell. The above two genes can be embedded in a harmless E. coli, as well as a gene of double-stranded RNA that can turn off the production of a certain oncogene (a protein that causes cancer). Such a bacterium enters the cell as a plague bacillus, is released as listeria and triggers an anti-cancer mechanism. Thus, another cancer drug recently tested on human cells is based on the use of our worst enemies.
Treatment of congenital blindnessLeber's amaurosis is a hereditary disease of the retina of the eye, leading to malfunction and subsequent death of photosensitive cells (rods and cones).
This is most often due to the lack of a working form of the RPE65 gene, without which the production of visual pigment is disrupted. Experiments on dogs and rodents, as well as subsequent studies on humans, have shown that it is possible to improve the vision of patients if a good copy of the gene is inserted into the cells of the retina of the eye. To do this, the RPE65 gene is embedded in an adenovirus, and then the virus is injected into the retina using a thin needle.
In particularly severe visual impairments, the cones and rods are completely destroyed. But in addition to the rods and cones in the eye there is a layer of nerve cells that process visual information and send it to the brain. While humans use a whole group of interacting proteins to recognize light, some unicellular green algae use a single protein, which is a light-sensitive ion channel that penetrates the cell membrane. If the channel is illuminated, it opens and lets positive ions into the cell, changing its electrical potential. If the cell is a neuron, a change in the potential on its membrane will lead to the appearance of a nerve impulse. The idea arose that it is possible to embed the gene of the light-sensitive channel of plants into the neurons of the eye to make them sensitive to light. In blind rodents, it was shown that after the injection of a virus containing a plant photosensitive channel gene, signals from the eyes begin to enter the visual parts of the brain.
The prospectsAnother approach is not to treat diseases, but to prevent them at the embryonic stages of development.
In part, this has already been implemented in the genetic diagnosis accompanying artificial insemination: you can choose an embryo devoid of known genetic diseases. In the future, scientists will learn how to use genetic engineering to improve and correct human genes. Another important point is that gene therapy forces us to reconsider our attitude to many natural enemies of man. Even dangerous viruses and bacteria can turn into our allies in the hands of an experienced genetic engineer.
Portal "Eternal youth" http://vechnayamolodost.ru12.05.2010