Half of yourself
What prevents us from reproducing by parthenogenesis and can we get around it
Polina Loseva, N+1
Rostombekov lizards from the South Caucasus have no males. They lay eggs alone. This method of reproduction — parthenogenesis — is practiced by many reptiles, various invertebrates, certain species of fish and amphibians, and in exceptional circumstances even some birds. Humans, like other mammals, do not behave this way — except for mythical characters like the ancient goddess Hera, who gave birth to Hephaestus "without knowing the love embrace." We have also learned to reproduce in unusual ways, for example, to have children "in vitro" and even to conceive them "from three parents". Can there be one parent?
On November 6, 1955, the British tabloid Sunday Pictorial published an unusual announcement: women were wanted, convinced that they had conceived their children without the participation of men. There was no reward for the "immaculate mothers" — only the satisfaction of personal curiosity and participation in a scientific experiment. And the idea of the experiment itself had arisen shortly before from geneticist Helen Spurway: she stated that people could theoretically reproduce by parthenogenesis — and suggested a way to test it.
Scientists have come up with two possible mechanisms of immaculate conception. Or it is an analogue of cloning, in which the embryo branches off from the mother cell and turns out to be a complete genetic copy of the mother. Either this is self-fertilization, that is, the egg merges with another germ cell or simply doubles its set of chromosomes alone. In any of the variants, the child gets only the genes of the mother — although, perhaps, not all. Therefore, Sunday Pictorial accepted applications only from "mom-daughter" couples, and preferably very similar to each other. After a thorough screening of such applications, 19 remained.
At the very first stage, London doctors, who were contacted by the newspaper's staff, screened out 11 couples. In them, as it quickly turned out, mothers did not have a very good idea of what "without the participation of men" meant (many thought that this meant pregnancy without violating the integrity of the hymen). Scientists took over the remaining ones — it was necessary to prove that the girls do not carry any "alien" genes in their cells.
They didn't know how to sequence at that time, so doctors had to be content with the signs of kinship known at that time — and check that the girls didn't inherit anything that their mothers wouldn't have. After the main blood groups (AB0 and Rh factor) were determined in all participants, four potentially parthenogenetic pairs remained. After testing for lesser—known antigens on the surface of red blood cells, there are only two. Another pair failed the eye color test: the mother's eyes were blue, and the daughter's were dark brown (usually the dark eye color gene dominates the light one, so if the mother had the corresponding gene, it would have manifested and made the eyes darker). There was only Emmimari Jones, who claimed that she conceived when she was treated in a hospital for rheumatism, where only women cared for her.
Test results for 9 additional antigens (blood groups) for four candidates for "immaculately conceived" mothers and their daughters. Pairs designated as Gamma and Delta failed the test. Beta had a chance (since the presence of the Leb antigen can be influenced by the AB0 blood group), but they were excluded because of the non-matching eye color. Only the Alpha pair remained in question. S. Balfour-Lynn / The Lancet, 1956
Emmimari and her daughter Monica experienced in several other ways. For example, doctors measured the concentration of blood group antigens in their saliva (not all people have them released into physiological fluids, this property is dominant). And they were also offered to try phenylthiourea — since the ability to feel its bitter taste is always inherited and well manifested. But on all points, mother and daughter completely coincided.
Finally, the researchers decided to test them for tissue compatibility and transplanted them along a skin section from Emmimari to Monica and vice versa. If the daughter carried someone else's genes, then the mother's body would quickly begin to reject her skin. As a result of the experiment, however, the flaps did not take root either on the mother or on the daughter: it fell off after a month from Emmimari, and the one from Monica lost its vessels in six weeks — and it was removed.
At this point, the doctors' experimental ideas ran out, and they concluded that they could not refute the hypothesis about the parthenogenetic origin of Monica.
Why is it impossible
Today, of course, it would be much easier to solve this problem, but no samples have been preserved since then. And scientists have stopped looking for examples of "immaculate conception" among people, having given up hope of finding something. This is because no one has yet met other parthenogenetic mammals — neither in the laboratory, nor even more so in the wild. So if Monica Jones really turned out to be a parthenogenote, it would become a sensation, not only in medicine, but also in zoology.
Mammals are prevented from reproducing alone by several barriers. The first of them is the immaturity of the egg. She spends most of her life — and this is decades, from the moment the embryo appears in the body to the maturation in the ovary of an adult woman — undeveloped. It has two sets of chromosomes that are ready to disperse — but do not diverge, therefore, it cannot be considered a full-fledged germ cell (it should have one set of chromosomes) in the strict sense. Even when an egg is sent from the ovary to the uterus, it is still in such a frozen state — until it meets someone who can bring it out of years of oblivion.
The fate of the egg. The upper row is maturation in the ovary, the first division: the first polar body separates, a double set of chromosomes remains, the cell prepares for the second division and freezes. The bottom row is after fertilization: the second polar body is separated, a single set of chromosomes remains, plus sperm chromosomes are added. Jurrien Dean / New England Journal of Medicine, 2016
In order to "turn on" the egg, you need to fill its cytoplasm with calcium, this will start division. Calcium is stored inside its organelles, but the "kingstones" open only on command — it is the sperm that feeds it. Merging with the egg, it triggers a signaling cascade, which first helps it to mature — that is, to bud off the second polar body. And then both sets — the male arriving in the sperm and the female receiving it — begin to prepare for the first division in the life of a new organism.
To take the situation into its own hands, without waiting for the sperm's command, the egg would have to learn how to generate the necessary signal on its own. Most vertebrate eggs do not know how to do this — and, for example, some fish that have embarked on the path of parthenogenesis have to accept a command from a sperm of another species. The egg lets in an alien sperm, and then throws out its chromosomes and further divides itself (this is called gynogenesis). So does the sperm of males of some fish that have mastered same—sex reproduction - it fertilizes the egg and pushes its nucleus out (and this is androgenesis).
Mammals have never been seen for such a thing. But from time to time, their eggs begin to multiply without the command of the sperm and not where it should be, in the fallopian tubes, but, for example, right in the ovary. So women may have a tumor consisting of different types of embryonic tissues — a teratoma. It can contain muscles, fat, bones, nerves and even teeth with hair. Sometimes a teratoma acquires the features of a real human embryo: with the beginnings of a head, tail, limbs and genitals.
Androgenesis in humans, by the way, also occurs. This happens if, before or after fertilization, the egg's own nucleus is destroyed. Then only the sperm that fertilized her (or even several) remains in her empty shell and replaces her maternal genes with her genes. The resulting cell begins to break up, but it does not grow arms and legs — just a cell mass is formed, which actively divides and can fill the entire uterus. This is called a bubble drift.
How the eggs manage to mature on their own and what becomes a push for them instead of a sperm is still unclear. But this effect is not difficult to reproduce in the laboratory — it is enough to treat the eggs with calcium. After this, the egg either does not complete its division and remains with a double set of chromosomes, or completes, but instead of discarded chromosomes makes a copy of those that were left alone. And then it begins to break up, as if it were really fertilized - at least, it turns out quite ordinary cellular balls—blastocysts.
Whether a healthy child can be born as a result of such an operation, and whether something similar has happened to Emmimari Jones is unknown. It is forbidden to plant such blastocysts in the mother's body, and it is impossible to grow them in the laboratory for longer than a certain period.
But experiments on mice show that artificial parthenogenetic blastocysts are not viable. Teratomas cannot become human either — even if they are remotely similar to him in outline, they still do not have a real placenta, and they cannot be taken out, they must be removed immediately. Parthenogenotes are prevented from surviving — at least in mammals — by another barrier: the father participates in the genetic upbringing of children, and not just "wakes up" the egg.
Parental control
Occasionally it happens that a newborn child does not get a paternal piece of the 15th chromosome: you have to use either a truncated paternal one or two maternal ones. And although the same genes are located on the maternal chromosome in the same place, they do not behave like the paternal ones (they are expressed, although they should not, or vice versa) — and therefore are unable to compensate for the loss. Children with whom this has happened are usually diagnosed with Prader-Willi syndrome — they are usually short, obese and other endocrinological disorders, often experience anger attacks, lag behind their peers a little in development and are almost all infertile.
Those who did not have enough of their mother's section of the 15th chromosome (and got, respectively, copies from their father) suffer no less, but in a different way. They develop Angelman syndrome: children are hyperactive and often laugh, but suffer from seizures and coordination problems (that's why it used to be called "happy doll syndrome") — and are usually even more retarded in development than people with Prader-Willi syndrome.
Genes that work differently depending on their origin are called imprinted, and the phenomenon itself is called genomic imprinting.
Why is this necessary?
Why mammals needed to regulate the work of genes in such a way can only be assumed. Most often, biologists associate this with the appearance of the placenta — which forced female mammals to invest even more resources in bearing cubs. This led to a conflict of the sexes: males became interested in their child "squeezing" the maximum out of the mother — since she may have the next offspring from someone else, with whom there is no need to share resources. Females, on the contrary, are interested in saving energy for the next batch of children. As a result, such a system has developed that allows you to maintain a balance of power.
For example: the embryo inherits the IGF2 working gene from the father — this is a growth factor that the placenta produces in order to expand and overgrow blood vessels. The maternal IGF2 gene is silent at the same time, but the IGFR2 gene works — it is a receptor that captures and destroys excess growth factor. These two genes compensate for each other, but as soon as one side overpowers the other, the balance is lost. Mice with only maternal genes cannot grow a normal placenta. Mice without maternal genes grow a huge placenta — but they cannot form a full-fledged embryo.
(A): experiments with nuclear transfer. Eggs into which two female or two male nuclei have been transferred do not produce viable embryos. (C): experiments with chimeric embryos. If 60 percent of the cells in the embryo are normal, and 40 percent contain only female or only male nuclei, then mice survive, but differ from ordinary animals in proportions. Valter Tucci et al. / Cell, 2019
More than 250 imprinted genes have already been found in humans. With Prader-Willi and Angelman syndromes, the child lacks literally several — and their absence somehow affects different organ systems. It is not difficult to imagine what will happen if you leave only the paternal or maternal genes to the child (even if you take them from two different fathers or mothers) — he will miss dozens at once. It is unlikely that such children will survive — as, in fact, parthenogenetic mice do not survive in the laboratory.
Daughter of mothers, child of fathers
But since the list of imprinted genes is approximately clear, you can try to select several key ones from them — and try to "tweak" their work in order to still get mammalian parthenogenotes. When scientists started trying it on mice, it turned out that it was enough to adjust only two genes: Igf2 and H19. However, it was not easy to do this. The researchers took immature oocytes (future eggs) from newborn mice — at this stage, the characteristic marks on the maternal genes have not yet been placed. A mutation was introduced into the genome of mice, which suppressed the expression of H19 and did not interfere with the work of Igf2. These oocytes were forced to merge with the eggs of an ordinary mouse and started division in them. Out of a couple dozen mice from two mothers, two survived until birth, one of them even became a mother.
Mouse Kaguya: the daughter of two mothers, she grew up and became a mother herself. Tomohiro Kono et al. / Nature, 2004
It took longer to tinker with the mice from two fathers. Spermatozoa were taken from one mouse. From another, embryonic stem cells were taken and forced to lose half of the chromosomes in order to remain with a single set. The genome of these cells was switched off in seven places so that they would not affect the expression of imprinted genes. After that, the scientists took an egg from the third mouse, already a female, removed the nucleus from there, injected two paternal nuclei: one from a sperm, the second from an altered stem cell. All these manipulations allowed us to get live mice from two fathers — however, they lived only two days.
This can not be called parthenogenesis in its purest form — after all, two individuals participated in them, albeit of the same sex. But even their offspring shows that this is not an easy and risky business. And at the same time, you can notice that it's still easier to do without a father than without a mother. Two fathers, in addition to editing the genome, also needed someone else's egg — so here we are talking more about another "child from three parents", although they participate in the appearance of a child in a different proportion than in the case of mitochondrial donation.
Almost Hephaestus
In 2017, two Brazilian scientists promised that soon we will know for sure whether parthenogenesis occurs in humans. Genome-wide sequencing, they explained, is becoming increasingly common (and recently the UK authorities gathered to read the genome of every third newborn in search of rare mutations and diseases). And if we are going to sequence genomes, then comparing them, it will not be difficult to catch a parthenogenote — as we managed to do with other animals.
And after experiments with mice from two mothers, they continued, it is already easy to imagine what set of mutations and breakdowns could allow a person to jump over parthenogenetic barriers.
You will need a mutation that disrupts the imprinting mechanism in eggs. Or at least that pair of mutations (or its analogues) that helped create mice from two mothers.
It is necessary to somehow stop the division of the precursor of the egg, that is, not to let it get rid of one of the sets of chromosomes. True, mammals have not yet encountered mutations that would lead to such a result — they have been found so far only in plants.
It is necessary to somehow activate such an egg, that is, to start its division and parthenogenesis proper. In mice, this is achieved by a mutation in the c-mos gene — and although it does not lead to such an effect in humans, it can be assumed that there are some analogues of it.
The last two barriers, however, are overcome by teratomas. And although they cannot become a child by themselves, individual parthenogenetic cells in the human body survive perfectly.
Three barriers that separate a person from reproduction by parthenogenesis — genomic imprinting, the need to maintain a double set of chromosomes, egg activation — and mutations that could help overcome them. Gabriel Jose de Carlia et al. / Medical Hypotheses, 2017
Doctors described the first semi-parthenogenetic boy in 1995. His parents brought him for an examination because of his asymmetrical face: the left half looked quite healthy, and the right one stood out with disproportionate features. After counting the chromosomes in the patient's blood cells, geneticists were surprised to notice two X chromosomes there instead of the X and Y ones. All of the boy's blood turned out to be "female" — while in the skin sample from his ankle, at least 95 percent of the cells were, as expected, "male".
The doctors did not calculate the ratio of the two types of cells in the rest of his body. Nor could they find out exactly what happened at the beginning of its development. But it was assumed that the egg was in a hurry with the first divisions: it separated the second polar body, doubled the chromosomes and managed to get detailed once before a sperm with the father's genome inside got to one of them. As a result, some of the boy's cells turned out to be standard, and some were "fatherless" with a double set of maternal chromosomes.
Bottom: boy, partial parthenogeny. Above: an assumed scheme of its origin. The egg activated itself, separated the second polar body (top row), divided into two cells (bottom right) and only one of them contained sperm chromosomes. Lisa Strain et al. / Nature Genetics, 1995
Then doctors found other patients who, presumably, could be partial parthenogenotes. For example, children who have part of the cells XX, and the other — XY, but each has paternal chromosomes. Scientists believe that this happened due to the fact that the parthenogenetic egg, which was activated by itself, was fertilized by two different spermatozoa during or after the first division (although other scientists believe that this is impossible, and we are actually talking about the fact that the egg was divided in a non-standard way). They also find children whose part of the cells carries only the paternal chromosomes — here, apparently, the chromosomes in the sperm were hastened to double, and after the first division, only dad's genes appeared in one of the resulting cells.
The fate of these people is hardly to be envied. Some of them are born hermaphrodites, others lag behind in development, and others suffer from tumors. However, this is exactly how we learn about their unusual combination of chromosome sets — when parents turn to doctors to consult about symptoms. So it's hard to say for sure whether parthenogenotes really can't be completely healthy or whether we just sequenced very few people.
Will we share?
International standards do not yet allow people to reproduce by parthenogenesis. However, they are changing rapidly — for example, scientists recently found it potentially acceptable to grow artificially created embryos longer than 14 days. But so far there is every reason to believe that even if someone manages to overcome all the obstacles on the way to parthenogenesis - both legislative and biological — it is unlikely that the result will be very viable.
Most animals try to avoid parthenogenesis for a reason: the second sex helps to mix genes in the population. Therefore, vertebrates completely abandon males only in extreme cases — for example, if a species was formed during the hybridization of two others, and the resulting females can no longer technically interbreed with anyone. Some may use parthenogenesis as a safety net in an extreme case. Such facultative parthenogenesis was previously found, for example, in domestic birds, and recently it was noticed in California condors, which had to breed in captivity as part of an ornithological program. Scientists suspect that "alternative" reproduction is turned on in birds in unfavorable conditions — if there is no suitable male around, the female has to cope alone.
But it is dangerous to abuse this: in the absence of males, females have to endlessly inherit the same set of chromosomes — and invent some alternative methods to create diversity (as, for example, invertebrate rotifers do by borrowing genes from other organisms). In addition, if a female divides her set of chromosomes in half, and doubles the remaining half, then her descendants will inevitably be homozygous, and for all genes at the same time. And all those problems that, with closely related crosses, "come out" after several generations, here can manifest themselves immediately in the first one. Perhaps this is why many parthenogenetic embryos in birds are not viable. The California condors that emerged from unfertilized eggs were also not in good health — although they looked completely normal outwardly — and died relatively early, leaving no offspring. And even Hephaestus, the parthenogenetic son of Hera, according to Homer, was born lame and sick, for which his mother threw him off Olympus.
So for people, parthenogenesis hardly looks like an attractive prospect. And you can turn it no more than once in a row: if the first generation of descendants gets a double set of identical genes, then the second generation will turn out exactly the same — that is, the result will be similar to cloning. Cloning people is still prohibited by international standards. But judging by animal experiments, we are much closer to this than to parthenogenesis. Therefore, people of the future who want to create a child in proud solitude, scientists would rather advise to reproduce themselves completely, not half. And we are gradually coming up with more and more cloning options.
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