How to change the embryo genome?
Genome editing at the zygote stage
Denis Rebrikov, "Elements"
Orphan diseases occur in a child due to a genetic disorder when the parents have the same mutation for a specific gene, both broken copies of which go to the child – one from the father and mother. The parents themselves are healthy at the same time, because they have only one copy of the gene broken and the second one is working. However, the child actually lacks one gene, and the function that he was supposed to perform is not realized. This leads to the development of a monogenic disease. The probability of the birth of such a child is 25%. If we know that the parents are carriers of a certain disease, then an in vitro fertilization (IVF) procedure is performed and an embryo is selected that does not contain the disturbed genes. Thanks to this, the future child will be healthy – in any case, he will not inherit a specific parental mutation.
Monogenic diseases and genomic editing
Sometimes, very rarely, we are unable to obtain a healthy embryo as part of the embryo selection procedure.: 100% of embryos, no matter how many of them we have, will carry violations, since both the father and the mother have a certain gene, that is, both parents have a monogenic disease. There are not so many monogenic diseases with which a person lives to the age when he forms a family and wants to leave offspring. For example, this is phenylketonuria (PKU) – a fairly frequent, but not very serious disease, which is well supported by therapy today. It occurs when the enzyme that breaks down the amino acid phenylalanine is disrupted. Such patients should adhere to a diet and take certain medications, but generally lead a normal lifestyle. Since phenylketonuria occurs with a frequency of 1 newborn per 5 thousand people, the probability of forming a family in which both people are sick with it (and, accordingly, all children born to them will have phenylketonuria) is 1 in 25 million. It seems that this is an infinitesimal quantity. Moreover, a man and a woman, knowing that they have the same hereditary disease, can decide not to start a family themselves.
However, there is a disease that increases the likelihood of forming a family of people with phenylketonuria – this is hereditary hearing loss. The fact is that deafness is genetically determined in most cases, that is, its occurrence is associated, for example, not with injuries received, but with genetic disorders recorded in the genes of breakdowns that lead to improper development of the auditory epithelium. Moreover, the most common variant of hereditary hearing loss is determined by one gene – GJB2, encoding the protein connexin 26. In 80% of cases of hereditary deafness, Russians have the same mutation in this gene.
Since people with such a disorder often communicate in their own language with each other, families within their community are formed more often than if it were by chance: social conditions work to ensure that such people meet and create a family. The risk of having a child with hereditary hearing loss in such a couple increases catastrophically. There are many families in Russia in which both a man and a woman carry the same disorder in the gene encoding connexin 26, and their children will also have a hereditary disorder. No preimplantation screening and IVF will allow you to choose an embryo that will develop into a child with normal hearing, due to the presence of a genetic disorder and the lack of combinatorics of healthy and broken genes.
In this case, you can try to fix the mutation at the stage of the first zygote cell, which is formed when the sperm and egg merge. The technology of directed DNA sequence modification is called genomic (gene) editing. Today it is so well developed that it is possible to repair the mutation directly in the DNA of the first cell from which the organism will develop.
Similar systems are being developed for some mutations. There are published scientific studies that demonstrate that such methods work. At the end of 2018, Chinese researcher He Jiankui announced that he had modified the embryo at the first cell stage. Two girls were born, whose gene encoding the receptor for which the human immunodeficiency virus clings has been changed. These children are genetically resistant to HIV and thus cannot get AIDS. The study received a lot of justified criticism: the scientist did not check the safety of the system and chose an inadequate clinical situation. Nevertheless, the first children with an altered genome at the stage of the first cell are already living among us, and there are no special problems with the development of these girls.
Security of genomic editing technology
The main question that worries everyone when it comes to including this technology in routine clinical practice is: how safe is it? Does it disrupt the genome outside of the place where we affect DNA? Let's say we got rid of a certain mutation in a gene and we can check the result even before transferring the embryo into a woman's body. But we also need to make sure that our actions have not led to other violations in any other place of the genome: no one forbids the system to change something else somewhere. Therefore, today the activity of scientists is aimed at checking the effectiveness and safety of genomic editors.
There are a number of approaches to evaluate these two indicators. In the next few years, the first drugs to correct mutations at the stage of the first cell will appear for practical use. There are situations when no child of a married couple can be born healthy, and parents must either accept that they will have a child with a violation, or take a donor egg or sperm. The solution that genomic editing offers is the way to ensure that children are born without a severe disorder.
Prospects of the technology of directed genome modification
The technology of correcting DNA disorders is being developed not only to solve problems with orphan diseases, which are extremely rare. When the technology is tested and begins to be used in cases with rare hereditary severe diseases, then, perhaps, scientists will show such its safety and effectiveness that we will try to use the same technology to correct the genes of predisposition to the development of other diseases.
There are many more situations when a couple's children will not be born with a severe hereditary disease, but, for example, will have a higher risk of developing cancer than the average population. And such parents will be offered to correct this at the stage of the first cell, thereby reducing the likelihood of developing cancer to a minimum.
Thus, most likely, in the future, technologies of directed genome modification will be used to correct disorders that determine hereditary predispositions.
About the author: Denis Rebrikov – Candidate of Biological Sciences, RNIMU named after Pirogov.
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