The third is not superfluous

Why does a child need an additional parent?

Sergey Sobol, Naked Science

Recently, the news spread around the world: the world's first "child from three parents" was born. However, already this August, the technique that was supposed to solve the problem of hereditary diseases was banned in the United States. We figured out why this technology is needed, and is this the first child with a third parent?

Dad, Mom... and mitochondria

The baby was born on April 6, 2016 in Mexico. His mother is a carrier of a rare genetic mutation, which, with natural fertilization, can lead to the development of Ley syndrome in a child. This is a fatal disorder affecting the nervous system, and they have not yet learned how to treat it. The genes whose mutation causes the disease are not in the nuclei of cells, where most of the genetic material is located, but in mitochondria – special components of the cell – organelles located in its cytoplasm and having their own genome. And, as you know, we get mitochondria only from the mother, those that are contained in the egg.

The mother of the child herself is healthy, but about a quarter of her mitochondria have a disease-causing mutation, due to which the woman suffered four miscarriages and lost her two previous children at the age of 8 months and 6 years. The new technique allowed her to give birth to a healthy boy. He inherited DNA from three people – his parents – and the mitochondrial DNA of a female donor. But about everything in order.

What are mitochondria and why do they have their own genome? In fact, they are not only in the mother's egg, but also in the sperm. In them, they provide activity and mobility on the way to the egg. However, after the fusion of the sperm with the egg, their death occurs. Actually, they are present in almost all cells of the body. The mitochondria is the energy station of the cell.

The structure of the cell / © wikimedia.org

Their main function is the oxidation of organic compounds and the use of energy released during their decay to generate electrical potential. Mitochondria synthesize ATP – adenosine triphosphate – a universal form of chemical energy in any living cell, in other words, fuel for our cells.

The number of mitochondria in a cell is not constant. There are especially many of them in cells in which there is a great need for oxygen. Brain, heart, muscles – their cells contain hundreds and even thousands of mitochondria. Mitochondria were first discovered in 1850 in muscle cells. In total, mitochondrial DNA contains 37 genes – 13 encode proteins, 22 - tRNA genes, 2 – rRNA. This is much less than the total number of genes in the human genome. Currently, it is assumed that the human genome contains between 20,000 and 25,000 genes. Thus, the number of mitochondrial genes is insignificant, which cannot be said about their significance.

There are not many organisms that can do without mitochondria. Mitochondria are present in plant and animal cells. It is all the more surprising to realize that they are strangers in our cells.

Mitochondria have been "living with us" for almost 2.4 billion years. It was then, during the oxygen catastrophe, that our unicellular and nuclear-free ancestors (prokaryotes) "tamed" bacteria capable of using oxygen to generate energy. Bacteria, the ancestors of our mitochondria, settled inside the cells and allowed them to adapt to the global change in the composition of the atmosphere. The increased content of free oxygen in it turned out to be disastrous for the vast majority of organisms of that time.In the process of such symbiosis, the once independent ancestors of mitochondria transferred most of their genes to the now formed nucleus of nuclear cells (eukaryotes). They kept only a part of their former genome for themselves. Moreover, this leap in evolution occurred, among other things, due to the increased energy efficiency of the cell. Scientists say that not only mitochondria have a similar symbiotic origin, but also, for example, chloroplasts, which also have their own DNA.

A modern example of such a symbiosis is Elysia chlorotica, a small sea slug belonging to gastropods, which literally turns into a photosynthetic animal before our eyes.

Genes, as we know, can undergo mutations. For various reasons, mutations in mitochondrial DNA occur much more often than in nuclear DNA. The consequence of this is mitochondrial diseases. And sometimes the rate of mutation in mitochondrial DNA also increases due to mutations in nuclear genes that encode enzymes that control mitochondrial DNA replication.Mitochondrial diseases lead to disturbances of energy functions in the cells of various human organs. Ley syndrome was described back in 1951 by British neuropsychiatrist Archibald Denis Ley. Children born with this syndrome never live to adulthood, and usually die at the age of several years. The disease affects both the brain and muscles. On average, this syndrome affects one surviving newborn out of 40,000. But in some regions this figure is much higher. For example, in the area of Saguenay-Lac-Saint-Jean, in central Quebec (Canada), one child out of 2,000 newborns is sick.

Was he the first?

The child, born last spring in Mexico, was named Ibrahim Hassan. His parents are a married couple from Jordan. They could not have healthy children for almost 20 years. They were helped to realize their dream by a team of embryologists from the New York Fertilization Center "New Hope" (New Hope Fertility Center) led by Dr. John Zhang (John Zhang).

In fact, Zhang is not the first to combine the DNA of three people in one embryo. In the 90s of the last century, several clinics in the United States have already performed similar procedures. Developed by the American scientist Jacques Cohen, the cytoplasmic replacement method allowed 30 to 50 children to appear who have "three parents". The names of some children even became known. For example, Alana Saarinen, who was conceived in the USA as part of an experiment on infertility treatment.

Alana Saarinen / ©bbc.com

But then the FDA (Food and Drug Administration) – the Food and Drug Administration – intervened and banned its use both because of ethical issues and because of safety concerns. This method was relatively simple, but had a significant drawback. He assumed the injection of the cytoplasm of the donor woman into the egg of the expectant mother. But in this case, the defective mitochondria of the mother are not removed from the cytoplasm, but only supplemented with healthy mitochondria of the donor. A mixture of different mitochondria, both healthy and sick, is formed in the child's cell. With further cell division, they are distributed randomly, and there is a possibility that defective maternal mitochondria may again outweigh healthy donor ones, and this will lead to the development of the disease. According to some reports, some of the children had developed genetic disorders.

Zhang's merit is that the child born last year was born thanks to a new technology. It is called "mother spindle transfer". He took the nucleus from the mother's egg and moved it to the donor egg, whose own nucleus was previously removed. The resulting egg with nuclear DNA from the mother and mitochondrial DNA from the donor was then fertilized with the father's sperm. Such a technique should make it possible to completely avoid the transfer of maternal mitochondria. Zhang's team used this approach to create five embryos, and only one of them developed successfully. This embryo was inserted into the woman's uterine cavity, and nine months later the baby was born. Such procedures largely repeat the technology of in vitro fertilization (IVF), when fertilization itself takes place outside the woman's body ("in vitro").

Two methods of modern mitochondrial therapy / © nature.com

Zhang's team carried out manipulations with cells in New York. After fertilization, the embryos were sent to Mexico to be implanted into the mother's uterus there. The procedure was performed in a hospital in Mexico, as such procedures are not allowed in the United States, and there is a legal vacuum in this area south of the Rio Grande.

Another method already approved in the UK is called "pronuclear transfer" and involves fertilization of both the mother's egg and the donor egg with the father's sperm. Before the fertilized eggs begin to divide, each nucleus is removed. The nucleus from the fertilized egg of the donor is removed and replaced by the nucleus from the fertilized egg of the mother. But for a couple from Jordan, this method was unacceptable, since they were against the destruction of embryos.

Between prohibition and permission

John Zhang had big plans for his methodology. He wanted to use it not only to protect the embryo from hereditary diseases, but also to solve the problem of age-related infertility. After the successful birth of a healthy baby, Zhang created the company Darwin Life, which was supposed to help women over 40 experience the joy of motherhood. One such procedure would cost clients $80,000-120,000.

Dr. John Zhang and the born child with "three parents" / © newscientist.com

However, on August 4, the FDA (Food and Drug Administration) sent a letter to the doctor demanding that he stop advertising the procedure he used. In its letter, the FDA reminded the doctor that it did not give permission for such manipulations.

Last April, Zhang requested permission from the FDA to conduct clinical trials. However, the FDA prohibits modifying a human embryo if its subsequent development is allowed. In addition, the experimental procedure is not considered completely safe. The boy who was born has not yet grown up, and it is still unclear how the experiment will affect his health in the future. But despite the lack of clinical trials, Zhang actively promotes his technique and promises to restore fertility lost with age. It was this fact that angered the FDA.

The only country in the world where artificial insemination with DNA from three parents is allowed is the United Kingdom. In February 2015, the House of Commons of the British Parliament, by a majority vote, allowed mitochondrial donation during artificial insemination. But the procedure for applying such procedures and the requirements for clinics to obtain permits for its use appeared only in December last year, when the British Committee on Fertility and Embryology (Human Fertilisation and Embryology Authority) began accepting applications from hospitals. The opportunity to use the procedure will be only for women who have a very high risk of having a child with a life-threatening mitochondrial disease. Doctors from the University of Newcastle, where this method of therapy was developed, are planning to get the first licenses. The procedures were supposed to begin this spring, and the first Britons with "three parents" should be born before the end of 2017.

The United States is also on the verge of legalizing the procedure. In February last year, the Committee on Ethical and Social Policy sent a report to the FDA on new methods to prevent the transmission of maternal diseases with mitochondrial DNA. His recommendations are likely to become the official policy of the American regulator.

Perhaps the first children with donor mitochondria will be exclusively boys. This restriction will be made specifically to exclude the transfer of donor mitochondrial DNA by inheritance to the next generation. There will be children with three parents, but there are no children with three grandmothers yet.

Thus, if the application of the technique has negative consequences, they will affect only the children born and will not be passed on to their future offspring.

Meanwhile, despite the fact that new methods make it possible to solve the problems of many families and their regulatory authorities, albeit cautiously, begin to resolve them, they also have opponents with ethical arguments. Editing the human genome takes us one step closer to consumer eugenics, says Dr. David King, a molecular biologist and founder of the public group Human Genetics Alert. "At one time, thanks to the irresponsible behavior of the scientific community, as well as with an obvious race for fame and profit, we allowed genetically modified products to appear, now it seems it's time to campaign for a global ban on human genetic engineering," says King. "When you start creating a society in which the children of rich people receive biological advantages over other children, the basic concepts of human equality are lost. Instead, you get social inequality written into the genes."

Portal "Eternal youth" http://vechnayamolodost.ru  11.09.2017