Recently, the world has spread the news: the world's first "child from three parents" was born. However, this August, the technique, which was supposed to solve the problem of hereditary diseases, was banned in the United States. We figured out why and who needs this technology, why it meets resistance, and is it the first child with a third parent?
Dad, mom … and mitochondria
The child was born on April 6, 2016 in Mexico. His mother is a carrier of a rare genetic mutation that, when naturally fertilized, can lead to the development of Leigh's syndrome in a child. It is a fatal disorder that affects the nervous system and has yet to be cured. The genes whose mutation causes the disease are not located in the nuclei of cells, where most of the genetic material is located, but in mitochondria - special components of the cell - organelles that are in its cytoplasm and have 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 experienced 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 donor woman. But first things first.
What are mitochondria and why do they have their own genome? In fact, they are present 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 found in almost all cells of the body. The mitochondrion is the powerhouse of the cell.
Their main function is the oxidation of organic compounds and the use of the energy released during their decay to generate an electric potential. Mitochondria synthesize ATP - adenosine triphosphate - a universal form of chemical energy in any living cell, in other words, the 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. It is currently estimated that the human genome contains between 20,000 and 25,000 genes. Thus, the number of mitochondrial genes in our country is insignificant, which cannot be said about their significance.
There are not many organisms that can do without mitochondria. Mitochondria are found in plant and animal cells. It is all the more surprising to understand that they are strangers in our cells.
Mitochondria "live with us" for almost 2.4 billion years. It was then, during the oxygen catastrophe, that our, still unicellular and nuclear-free, ancestors (prokaryotes) "tamed" bacteria capable of using oxygen to generate energy. Bacteria, the ancestors of our mitochondria, settled inside 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 detrimental to the overwhelming 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 formed nucleus of now nuclear cells (eukaryotes). They left for themselves only a part of their former genome. 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 photosynthesizing animal before our eyes.
Genes are known to be mutated. For various reasons, mutations in mitochondrial DNA occur much more often than in nuclear DNA. The consequence of this is mitochondrial disease. And sometimes the rate of mutation in mitochondrial DNA is also increased due to mutations in nuclear genes that encode enzymes that control mitochondrial DNA replication.
Mitochondrial diseases lead to impaired energy functions in the cells of various human organs. Leigh's syndrome was described back in 1951 by the British neuropsychiatrist Archibald Denis Leigh. Children born with this syndrome never reach adulthood, and usually die by the age of several years. The disease affects both the brain and muscles. On average, this syndrome affects about one in 40,000 newborns who survive. But in some regions the rate is much higher. For example, in the Saguenay-Lac-Saint-Jean area in central Quebec, Canada, one in 2,000 newborns is sick.
Was he the first?
The child, born last spring in Mexico, was named Abrahim Hassan. His parents are a married couple from Jordan. They could not have healthy children for almost 20 years. They were helped by a team of embryologists at the New Hope Fertility Center led by Dr. John Zhang.
In fact, Zhang is not the first to combine the DNA of three people into one embryo. In the 90s of the last century, several clinics in the United States already performed similar procedures. The method of cytoplasmic replacement developed by the American scientist Jacques Cohen allowed 30 to 50 children to appear who have "three parents". The names of some of the children even became known. For example, Alana Saarinen, who was conceived in the United States as part of an experiment to treat infertility.
But then the Food and Drug Administration (FDA) stepped in and banned its use for both ethical and safety reasons. This method was relatively simple, but had a significant drawback. He proposed the injection of the cytoplasm of the donor woman into the ovum of the expectant mother. But in this case, the defective mother's mitochondria are not removed from the cytoplasm, but only supplemented with healthy donor mitochondria. A mixture of different mitochondria, both healthy and diseased, is formed in a child's cell. With further cell division, they are distributed randomly, and there is a possibility that defective maternal mitochondria can again outweigh the number of healthy donor ones, and this will lead to the development of the disease. According to some reports, some children developed genetic disorders.
Zhang's merit is that the child born last year was born thanks to new technology. It is called "maternal spindle transfer". He took the nucleus from the mother's egg and transferred it to the donor egg, whose own nucleus had previously been removed. The resulting egg with nuclear DNA from the mother and mitochondrial DNA from the donor was then fertilized with the father's sperm.This technique should completely avoid the transfer of maternal mitochondria. Zhang's team used this approach to create five embryos, and only one of them developed safely. This embryo was inserted into the woman's uterus and a baby was born nine months later. Such procedures in many respects repeat the technology of in vitro fertilization (IVF), when fertilization itself occurs outside the woman's body ("in vitro").
Zhang's team performed cell manipulation in New York. After fertilization, the embryos were sent to Mexico to be implanted in the mother's uterus. 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 fertilizing both the mother's egg and the donor's egg with the father's sperm. Before 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 married couple from Jordan, this method was unacceptable, since they were against the destruction of the embryos.
Between prohibition and permission
John Zhang had big plans for his technique. 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 successfully giving birth to a healthy baby, Zhang created Darwin Life to help women over 40 experience the joy of motherhood. One such procedure would cost clients between $ 80,000 and $ 120,000.
However, on August 4, the FDA (Food and Drug Administration) sent a letter to the doctor demanding that he stop advertising his procedure. In its letter, the FDA reminded the doctor that it did not give permission for such manipulations.
Last April, Zhang asked the FDA for approval to conduct clinical trials. However, the FDA prohibits the modification of the human embryo if its subsequent development is allowed. In addition, the experimental procedure is not considered completely safe. The born boy has not yet grown up, and it is not yet clear how the experiment will affect his health in the future. But despite the lack of clinical trials, Zhang is actively promoting his method 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, authorized the donation of mitochondria during artificial insemination. But the procedure for applying such procedures and the requirements for clinics to obtain permits for its use did not appear until December last year, when the British Human Fertilization and Embryology Authority began accepting applications from hospitals. Only women who have a very high risk of having a child with life-threatening mitochondrial disease will be able to use the procedure. The first doctors plan to obtain licenses from the University of Newcastle, where this method of therapy was developed. The procedures were to begin this spring, and the first three-parent British are due to be born by the end of 2017.
The United States is also on the verge of legalizing the procedure. Last February, the Ethics and Social Policy Committee submitted a report to the FDA on new ways to prevent mitochondrial DNA transmission of maternal diseases. 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 limitation will be made specifically to exclude the transmission of donor mitochondrial DNA by inheritance to the next generation.There will be children with three parents, but no children with three grandmothers yet.
Thus, if the application of the technique has negative consequences, then they will only affect the children who are born and will not be passed on to their future offspring.
Meanwhile, despite the fact that new methods allow solving the problems of many families and, albeit cautiously, but beginning to resolve the regulatory authorities, they also have opponents with ethical arguments. Editing the human genome takes us one step closer to consumer eugenics, says Dr. David King, molecular biologist and founder of the Human Genetics Alert community group. “In the past, thanks to the irresponsible behavior of the scientific community, as well as the obvious race for fame and profit, we allowed genetically modified products to appear, now it seems that it is time to campaign for a global ban on genetic engineering of humans,” says King. “When you start to create a society in which the children of wealthy people gain biological advantages over other children, the basic concepts of human equality are lost. Instead, you get social inequality written in the genes."