Hidden risks of mitochondrial donation
Alexandra Bruter, <url>
Another round of controversy unfolding around mitochondrial donation (Garry Hamilton, The hidden risks for ‘three-person’ babies) has hit the pages of Nature magazine. Apparently, this is due to the fact that a permit for the procedure issued by the British Parliament is due to come into force this month.
Mitochondrial donation is an assisted reproductive technology. It should help give birth to healthy children to women with genetic diseases caused by errors in the mitochondrial genome. It is believed that when fertilizing an egg, the sperm brings only the nuclear genome into it, all other parts of it are left out. Thus, all human mitochondria are descendants of mitochondria that were in the egg at the time of fertilization.
Mitochondria are the most "independent" of the organelles of animal cells: they have their own genome encoding, however, not all the proteins necessary for mitochondria to work. Some genes still moved from there to the main, nuclear genome of the cell. There are 37 of them left in the mitochondrial genome.
Mitochondria provide the cell with energy in a convenient form by synthesizing ATP. The form of energy storage is a very fundamental thing. If your car has a gasoline engine, the presence of a waterfall, a nuclear power plant or a power line next to it will not help it move. Even a can of gasoline standing in the trunk will be useless until you pour gasoline into the tank. While the cell is alive, chemical reactions in it reduce entropy, and, therefore, require energy expenditure. For example, the transport of many substances inside (or outside) the cell requires energy. As a rule, the enzyme, which is a channel in the membrane, has a site whose spatial structure allows it to contact the ATP molecule. After that, one of the chemical bonds in the ATP molecule breaks (adenosine triphosphate turns into adenosine diphosphate – ADP), the spatial conformation of the protein changes, and this change allows the substance to overcome the cell membrane.
A lot of enzymes in the cell work this way, and in their structure there is a fragment interacting with ATP, no other molecule will replace it. It is not surprising that deviations in the work of mitochondria synthesizing this very ATP can cause a variety of diseases.
ATP synthesis occurs on the mitochondrial membrane. This process resembles the operation of a proton pump in reverse. An electron with high energy moves along the transport chain to a position with lower energy, so this movement is spontaneous. Due to the electric charge, spontaneous proton transfer through ATP synthase is associated with it, the principle of operation of which is opposite to the proton pump. Protons pass through it spontaneously, and due to the energy of their passage, a chemical bond is formed between adenosine diphosphate and another phosphate group and ATP is obtained (or adenosine monophosphate and a phosphate group to produce ADP).
All these processes occur in eukaryotes on the mitochondrial membrane, and in bacteria – just on the cell membrane. This fact, along with the fact that mitochondria have their own genome, led scientists to believe that mitochondria are bacteria that have chosen symbiosis with the emerging eukaryotic life form. In addition, inside the mitochondria there are their own protein synthesizing machines – ribosomes, much more similar to bacterial ribosomes than to eukaryotic ones. Photosynthetic organelles - plastids – apparently have a similar origin in plants, algae and some protozoa.
The catch is that due to the independence of mitochondria and the importance of their functions, genetic defects quickly become visible and, starting from some point, cannot be eliminated by themselves. Mitochondrial DNA is transferred to daughter mitochondria without any recombination.
Imagine that a woman has a mutation in the DNA of one of the mitochondria. That's where it all starts – one mutation in one mitochondria. If this mitochondria is not in the germ cell, it has no chance of being inherited, no matter how it reproduces. But, let's say, the defective mitochondria still ended up in the egg. There are several hundred thousand mitochondria in an egg, and, most likely, a defective one will need several generations for its descendants carrying the mutation to make up a significant percentage of mitochondria. While there are few of them, a miracle can always happen – only normal mitochondria can get into future germ cells, and there will be no hereditary transmission. But as soon as there are a lot of defective mitochondria, there is nowhere to go – they will be transmitted through the female line as long as there are descendants through the female line. The distribution of defective mitochondria trapped in the egg into the tissues of the future organism is quite random, and the symptoms of diseases depend on where exactly they get to. The most severe conditions, as a rule, are caused by the ingress of defective mitochondria into the nervous and muscular tissue – they need the most energy.
If abnormal mitochondria got mainly into future eggs, an outwardly healthy woman may have seriously ill or completely unviable children. Every year, several thousand such children are born in the world. Donor mitochondria, or rather, donor eggs, can help families. The nuclear genome will be removed from the donor egg, the nuclear genome of the mother will be inserted, and she will be fertilized by the father's sperm.
From a technical point of view, all manipulations are well-developed and do not carry the risk of new pathologies of embryo development. In 2000, when the procedure had not yet been banned in the United States, the first child with donor mitochondria was born to a mother with a genetic defect in mitochondria. The girl's name is Alana Saarinen, according to her parents, she leads a normal lifestyle and feels great. Despite this, the procedure was banned by the FDA due to doubts about ethics and safety. The ban in the US has not yet been lifted.
The Parliament of the United Kingdom in February this year allowed mitochondrial donation. The permit should come into force in October, that is, in the very near future. What are those who speak out against afraid of?
Doubts about the safety of mitochondrial donation have both theoretical and experimental reasons.
Proteins encoded by the mitochondrial genome should interact not with each other in a vacuum, but with other cellular proteins, including those encoded by the nuclear genome. Interactions between proteins are usually determined by the spatial structure of proteins, and replacing a single amino acid can disrupt the interaction. It is assumed that mitochondrial genes are coordinated with nuclear ones, and the proteins synthesized on their basis interact as they should. Scientists who propose to postpone donation say that mitochondrial replacement can lead to misalignment of genomes and disruption of interactions necessary for the vital activity of the cell.
In the 90s, an experiment was conducted in France with two strains of mice: H and N. Their mitochondrial genomes were slightly different, and it was known that H mice learn to navigate the maze faster than N. Scientists swapped mitochondria for mice: N mice with h mitochondria and H mice with n mitochondria turned out. By launching new mice into the maze, the scientists found that Hn mice began to navigate the maze more slowly, but Nh did not navigate faster at all, they remained almost the same as they were. Changes in behavior were also accompanied by changes in the anatomy of the brain. This was the first study to show that mtDNA variations, which were considered neutral until now, can have a significant impact on behavior and well-being.
A similar experiment was conducted on fruit flies. Flies of one strain were crossed once with females of a strain with different mtDNA, and the resulting new generation was left to cross with representatives of the original strain. A few generations later, the researchers obtained flies whose nuclear genome was slightly different from the original one, and the mitochondrial genome was alien. After that, flies with an identical nuclear genome, but different mitochondrial ones, were placed together and began to see what would happen. It turned out that flies with old mtDNA lived longer and adapted better than those with artificially introduced. From this it could be concluded that the old DNA is better than the new one, if not for the results of the reverse experiment. When the strain that served as a mitochondrial donor in the previous experiment had mitochondria replaced with the mitochondria of the recipient strain in the first experiment, the picture turned out to be similar: "their" mitochondria provided flies with better competitiveness than others. The conclusion follows from all this: it is not important which gene variants are encoded in mtDNA, but how they combine with the rest of the fly.
Similar phenomena have been found not only in experiments with laboratory animals, but also in the wild. Two related populations of copepods with similar nuclear genomes, but very different mitochondrial ones, were found on the Pacific coast. They can interbreed independently in the wild, but such offspring usually do not feel very well. It turned out that their ailments are just related to metabolic problems. Moreover, when sick females born in a "mixed marriage" were crossed with healthy males from the population of their mothers, the offspring turned out to be healthy. That is, when the right combination of mitochondrial and nuclear DNA was restored, metabolic problems disappeared.
Is it possible to transfer the results of these observations and experiments to the question of mitochondrial donation? And, if so, what conclusions follow from this?
The genetic diversity of humans is much higher than linear mice or fruit flies (linear laboratory animals are almost identical in general). Over the past few hundred years, people have been moving around the globe quite actively and intermarrying with representatives of other peoples and races, creating new genetic combinations. At the same time, no evidence has yet been found that, if we abstract from the social aspects, children from mixed marriages feel worse and suffer from metabolic disorders that are not characteristic of their purebred peers.
The mitochondrial DNA of humans is well studied and classified: similar variants are combined into haplogroups. While there are doubts about the safety of combining genomic DNA with arbitrary mitochondrial DNA, it is possible to select a donor with mtDNA of the same haplogroup as the recipient. British doctors are going to do just that.
For many families, donor mitochondria are the only way to give birth to their own living and healthy child. Of course, there are surrogate mothers, the opportunity to adopt a child, or even you can, when faced with difficulties, abandon the idea of having a child altogether. But many people will consider such a price for getting rid of a danger that probably does not exist too high. It will take a little more time to demonstrate the safety of the method more clearly. But even now, the option of donating within one haplogroup seems to be a win-win.
Portal "Eternal youth" http://vechnayamolodost.ru
05.10.2015