Children of the future: Why edit genes and select embryos
Some time ago, the world was shocked by the news that Chinese scientists for the first time managed to correct a mutation in the human embryo gene - quite simply, edit it. Many were worried: the possibility of such a technology immediately draws a frightening picture of genetic discrimination, the stratification of society and, in the worst case, Gattaki. Scientists, however, pursue a simple goal - the treatment of hereditary diseases. This technology will still be tested in the coming years, and perhaps even decades, but there are already ways in the world to fight genetic diseases. We talked with Ekaterina Pomerantseva, Candidate of Biological Sciences, Head of the HSCI DNA Diagnostics Laboratory, about why we should select embryos, why infertility is stigmatized and whether we should be afraid that everyone will soon make children to order.
Why do we need to analyze genetic mutations?
In Russia, the situation with genetic diagnostics is the same as in the rest of the advanced world fifty years ago: people learned that they have a high risk of a hereditary disease, because they had a sick child. In the 21st century, this is certainly not the right way to learn about genetic risks. Technologies allow to learn about them in advance with the help of screening and confirming its diagnosis. Anyone who wants children, it is advisable to do an analysis of clinically significant mutations. Each person, according to modern estimates, must have 15-20 mutations of those that lead to severe hereditary diseases. If such mutations are found, then there is a choice: preimplantation diagnosis or prenatal (already during pregnancy), sometimes - the use of donor sperm or eggs. Changing a partner formally, by the way, is also a way to prevent the birth of a sick child in such a situation, but, fortunately, no one else does.
A simple rule works here: it is better to check at least somehow than not to check it at all. For very little money, for example, you can do the simplest karyotyping when looking at chromosomes. This is a genetic method that has existed for a long time, since the beginning of the 20th century. When chromosomal rearrangements are often habitual miscarriage, infertility, the birth of sick children.
There are testing for individual, but very significant mutations, such as one that leads to spinal amyotrophy - one of the most common rare diseases. Every 30th person is the carrier of this mutation. This is a recessive disease, for the manifestation of which it is necessary that two copies of the diseased gene are met. Therefore, in a family where each of the parents has a mutation in one of two copies of the gene, the probability of having a sick child is 25%. Spinal amyotrophy is incurable, and most children die because of it during the 1-2 year of life.
Checking for carriage of this disease costs about 5-7 thousand. Taking into account the average income, for example, in Moscow, the very risks of a serious illness and the fact that it is necessary to do a test once in a lifetime, I do not think that it is expensive. A person does blood and urine tests hundreds of times over his life, and not always for free, although cheap - in the end, a decent amount is accumulated. All genetic analyzes are done once, the only question is how far they are deployed. As a rule, it is possible to find a balance of price and information content depending on the life situation.
If the family already has one sick child and the parents are looking for the cause of his illness, then the most detailed methods are offered. If there is a desire to clarify whether there is an increased hereditary risk, then we can confine ourselves to tests that are simpler and less expensive. We, for example, have such a test, called "Ethnogen": there are about 250 mutations and about 60 genes in it, we tried to select the most frequent and clinically significant. Hereditary diseases are relatively rare, because there are a lot of genes and mutations, and, most often, when we combine our germ cells, our mutations simply do not occur with mutations in the same partner genes and do not manifest themselves.
When it comes to childbirth, it is necessary to be checked for mutations that are associated with the risk of serious serious hereditary diseases, and not for optional nonsense. Nowadays, “genetic tests”, which are not so much related to clinical genetics, as entertaining, have become fashionable: tests for sports indicators or a tendency to obesity, and so on. They have a confirmatory scientific base, but they do not influence decision making, at least I very much hope that no one will refuse to give birth to a child because he has an increased risk of being prone to obesity. We do diagnostics when it comes to severe, usually incurable diseases. If the future child can be cured, then you need to give birth and treat, and not to engage in the selection of embryos.
Preimplantation genetic diagnosis
Preimplantation genetic diagnosis (PGD) is the diagnosis of hereditary diseases in embryos. Using a biopsy, take one or more cells from embryos obtained by IVF, and check them for genetic abnormalities. Doctors can recommend PGD if the patient is at risk, but, first, not all doctors know what these groups are, and secondly, PGD is technically very difficult, so only very large centers can afford to open their laboratory. . Only 2% of all IVF cycles in Russia are accompanied by PGD.
PGD of specific, monogenic, hereditary diseases is needed for those people who have a high risk of specific genetic abnormalities. If such families choose to perform prenatal, rather than preimplantation, diagnosis, then with an undesirable result, an abortion has to be done - which is always a traumatic experience. The second group of patients are those who need to diagnose chromosomal abnormalities. In this case, we are not talking about specific mutations, but about an increased risk that chromosomes will diverge incorrectly. This applies primarily to families of late reproductive age, and the age of a woman has more significance. When diagnosing, we take a sample from the embryo cell and compare the number of all chromosomes with the reference normal set. If the embryo is abnormal, then we see extra or missing.
The method we use is called comparative genomic hybridization, and it is good at identifying such disorders. They are quite common: about 50 of the embryos that come to us for analysis have chromosomal abnormalities. Not all embryos that are laid in humans are chromosomally safe, and even in normal pregnancy it is possible that an embryo with an abnormal chromosome set will fall. A woman may not even notice pregnancy at the same time: it seems that a small cycle failure occurs, but in fact it was a small pregnancy that naturally broke off very early.
What has been achieved in China
In the end, our activity is to ensure that a healthy child is born instead of a sick child. The selection described above is one way to achieve this. But there is another option: those embryos that are, change so that they become normal. The household name for this is genome editing. Now there are good technologies that allow you to do this quite effectively, including the CRISPR / Cas9 technology. What they did in China: they took a human embryo and replaced the gene that leads to cancer mutations in the breast and ovaries with a normal one. The embryo, of course, was not transferred into the uterus, so that its development, as expected, stopped on the 6th day.
In China, this is allowed. In the rest of the world, after that, they began to fuss - most of all those who were engaged in CRISPR / Cas9 technology, but not on embryos, but on samples of cells isolated from peripheral blood. This is the so-called ex vivo gene therapy, when cells are taken from peripheral blood, leukocytes are taken, they make certain genetic changes, and then they are transplanted back. In this way, some diseases related to the work of the bone marrow can be treated. The people who are engaged in this, were afraid that gene therapy will now be shut down all, and to prevent this, they made a call to ban specifically work with embryos. In the States, such experiments have been banned.
The main question regarding the CRISPR / Cas9 technology or what they have done in China is how much or little they create new mutations besides those that they correct. With any gene therapy there is such a danger. At one time, gene therapy was very severely inhibited by one very negative clinical case: the child was treated for some hereditary disease, but in parallel with the corrections in the cells some other mutation occurred, which caused the child to develop blood cancer. After this, gene therapy began to develop much more slowly than it could, because it was too early to launch the raw technology into clinical use.
CRISPR / Cas9 technology is in the process of analysis. In order to find out if it is accurate enough, a huge amount of scientific work is carried out. In China, it was crucial to show that editing a human embryo is possible. Further there will be a long period when this technology will confirm its effectiveness, safety, accuracy and so on. When it turns out that everything is fine at 99 хорошо, then, most likely, it will be possible to use it.
Will there be a world where all the children will be made to order?
We cannot help those who want the “ideal child” - we simply will not work with them. In addition, many things that people want are often simply impossible in terms of technology and professional ethics. I already mentioned one example - when diseases are curable. Also, people get rejected if they want a child with a deliberate abnormality. For example, in a deaf family it is easier to raise a deaf child. In a family that grew up in an English village, where almost all people are stunted because they have a hereditary form of dwarfism, they do not want a child of normal height, who will not enter the door. These are real stories from world practice. In Russia, by the way, people are much more committed to a certain concept of "norm" and there are no such requests.
The only questionable request that is relatively common in Russian practice is a certain sex of the child, but this is also unethical and prohibited by law, except for situations where the disease is associated with a specific sex. The question of the ethics of selection by gender is quite complex, and in some countries, the same USA, they do it. We were banned because they were afraid that everyone would want boys, as it has been for a long time in China and India. They had a very strong bias: the girls were selectively aborted, and then they began to be selected for PGD. In the United States, despite the fact that sex selection is allowed, it occurs approximately equally in the direction of boys and girls in order to support gender balancing in the family.
It should be understood that people have long and without assisted reproductive technologies can choose their own children with desired properties. This method has existed for many, many years - and this is nothing but the choice of a partner with attractive signs for us. Thus, people themselves throughout history carry out genetic selection. Whether, over time, there will be an additional selection mechanism for this, not only by the type of partner, but also by the partner's genes, is possible, but I doubt it. First, PGD is a medical procedure. It is unlikely to find a doctor who would like to participate in the history of creating an ideal person - not for that people go into this profession. Secondly, it is a high-tech method that requires special equipment and personnel.
Thirdly, purely for biological reasons, it is impossible to unambiguously diagnose multifactorial complex traits in an embryo. Imagine that there is a trait that depends on a single gene. For example, cystic fibrosis depends on the CFTR gene. The risk for each embryo is 25. If we check 10 embryos, which, by the way, still need to get, because with IVF, as a rule, they get less, then on average two and a half of them are sick, and the rest are healthy. Imagine that there are two genes at once that affect the manifestation of a certain trait, respectively, you will need even more embryos to choose among them, and so on.
The more genes affect the manifestation of a trait, the more embryos we need to check to find the perfect combination. If 10 genes have to line up in a certain way in order to get, say, a certain intelligence, then where do we get so many embryos? This is a biological limitation: most complex traits - intellect, beauty, charm, talent - are difficult to encode. Super children are the work of teachers and parents, although intelligence depends on genes quite strongly, not only from one but from many, and you will not find a doctor who will make a selection based on this feature.
Is it possible to make a child from parents of the same sex or three parents?
Children from three partners is a deceptive language. From the third person, only mitochondria are taken, in which the amount of DNA is scanty, so to consider him as a parent is approximately like a person after a bone marrow transplant to be considered the “child of three parents”. The technology of using donor mitochondria is not new, it was developed several years ago and recently improved. The meaning of the method is to increase the likelihood of having a healthy baby in a family where the risk of mitochondrial disease is high.
Mitochondria are structures that provide the cell with energy, and if their work is disrupted, diseases affecting various organs develop, especially those with a high level of metabolism. Severe, disabling or fatal diseases for which there is no treatment. The use of donor mitochondria for such a family is simply salvation, and such children have already been born. Legally, this is not specifically regulated yet, and I don’t see at all that it can be forbidden, this is a normal medical technology, if you don’t chase names that tickle your nerves.
With a child from parents of the same sex is a completely different situation. This, alas, is purely biologically dangerous. To work properly, genes must be inherited from women and men, otherwise there will be big problems. There is such a class of hereditary diseases - imprinting diseases. They arise when, due to mutation, two copies of the gene are from one parent, and from the second, nothing. So, developing a technology for obtaining embryos from parents of the same sex means knowingly taking the risk of having a sick child. If a same-sex couple wants a common child, then they can raise it together, and the donor cells are better used for fertilization. I am for biosafety.
Ethical selection
I don’t think that there is a problem with ethics if our goal is correct. The birth of a healthy child instead of a patient, from my point of view, is exactly that. Rather, it is not about whether our methods are ethical, but about how accurate our technologies are. If the technology that we use is poorly developed and can lead to side effects, then it should not be used, it should be refined. But in general, I do not see anything unethical in making a healthy embryo from a diseased embryo. Not all things that at first glance seem unnatural to someone are actually unacceptable. The situation when a child with Down syndrome goes to a group of ordinary children in kindergarten will also seem unnatural to someone - although in fact it is correct. We must push the limits of our tolerance so that progress can benefit people.
As for the use of human material, as was done in China, everything usually comes down to the question: from what moment should a biological object, obtained from germ cells, be considered a living organism and a human? There are many different approaches. There is a religious, very convenient, but very conditional - who comes up with the terms, on the basis of what? People who adhere to one religion may consider that the embryo becomes a man from the 12th week, in other religions - that as soon as it is transplanted into the womb, and in the view of the Orthodox Church with the embryo, nothing can be done from the very beginning, as soon as the egg is fertilized. For a person who has seen how an embryo looks at this stage, it is rather difficult to consider him a person. You see a conglomerate of 8 cells, and it is much more similar to what you see under a microscope when you do a blood test, rather than a person.
PGD Consulting
A very important part of our work is PGD-consulting, which covers medical, genetic, managerial issues; we must make sure that all adjacent chain links work properly. The consultant conducts analytical and organizational work in the interests of the patient, so that he does not do anything superfluous, but does the necessary in the most correct way. Например, если семья хочет понять, нужна ли ей ПГД, то мы изучаем анализ, запрашиваем исходные данные, заново анализируем, общаемся с экспертами и делаем вывод.
Другой вариант: есть ребенок, которого можно вылечить при помощи трансплантации костного мозга, но нет доноров. In Russian practice, it often happens that doctors recommend giving birth to a second one, so that he is a donor for the first child with Fanconi anemia, and they say nothing about the second risk of the same disease is 25. Here it is important that the child is born not only tissue-compatible, but also healthy, and then there are experts who would be willing to use healthy stem cells to treat a sick child. It is important that in order to obtain them there is even no need to take the bone marrow from the child - instead, as a source of stem cells, they use umbilical cord blood, which is discharged from the cut part of the umbilical cord during birth, so this is a harmless, non-invasive procedure.
It is important to psychologically support patients. In the USA, for example, an PGD consultant is required to have an education not only of genetics, but also of a psychologist. The inability to have a child, or a healthy child, causes the family more psychological and social problems. Partners immediately begin to look guilty. The most important thing is to explain that the term "fault" is not applicable here at all. Infertility is a disaster that patients face as a family, and they have to become a support resource for each other.
It is very important that families also have external support, since the PGD consultant is temporary in their lives. It is important that there are structures that will be close throughout life, if required. If a child is born with a hereditary disease, the counselor must find out what kind of aid societies, forums of parents of such children and such children themselves are. The information that there is someone who knows about this firsthand, significantly affects the quality of life of the family. This is still not very widespread in our country, and we are working hard to change this paradigm. In Russia, things are not very good: for a doctor in the framework of the modern formal system, this is an “extra” time spent in which he could receive a couple of patients.
For example, I talked with a family in which the man had azoospermia, that is, there were no sperm cells at all. He wondered: am I the only one? It is clear that not one. Men with such a problem are not so few, but they do not discuss it among themselves - even anonymously on the Internet. This is partly due to the fact that in our culture the state of health is necessarily tied to a way of life: it is considered that if a person has some problems, he is always to blame for them. This is completely wrong. People are embarrassed, although the opportunity to talk with another person about this in terms of benefits is no less significant than medicines and so on.
Stigmatization of infertility and IVF
Infertility is a very common problem. How many people, from those that you know, talked about their infertility? Every tenth family has no children, not because they do not want, but because they cannot. If you have 100 friends, it is possible that 10 of them are fruitless. Do you know about this? Not. Because it is a very intimate sphere and a stigmatizing diagnosis. This, in particular, is strongly influenced by the position of the church on this issue. Until it is believed that infertility occurs among those who lead a sinful lifestyle, people will be afraid to talk about it. As long as people are afraid to talk about it, there will not be enough public attention to the significance of this problem. And if no one knows about it, there will not be enough funding to solve it.
The inability to have children or the need to use aids such as IVF changes a person. People unfairly begin to feel inferior. In every Moscow sandbox children born with IVF play. But few parents are ready to talk about it. They can be understood: even doctors are prone to prejudice when it comes to such children. In such children, often any health problem is blamed on IVF - instead of having a full diagnosis. A vicious circle of myth arises: first they say that all the problems are due to IVF, and then they say that because of IVF, these problems have become more.
Problems of the Russian health care system
There is an expression "punitive psychiatry". I once came up with the term "punitive gynecology", and it seems to me that it is fully applicable to Russian medicine so far. This is the situation when a woman stops feeling like a normal person: she is afraid to go to a gynecologist, she expects a degrading attitude, talking about her problems, and she does not feel confident during a medical examination. Yes, the situation has improved due to the fact that women have the opportunity to choose between a public and private clinic. But for many, this choice remains inaccessible, as it is associated with high financial costs, and sometimes you have to face the state system.
At the same time a few years ago there was a remarkable shift towards normal assisted reproductive medicine: IVF began to be provided from the state budget under the OMS (Compulsory Health Insurance Policy). This is a fantastically good undertaking, but some time ago I heard the disturbing report of a doctor who said that they do not consistently choose a quota for OMS in their clinic. Patients are afraid to go to IVF on OMS, firstly, because it requires a conclusion from the antenatal clinic, where no one even wants to step foot, and secondly, they fear a disrespectful attitude, extorting bribes and just sending to a bad center. In fact, the quotas are large, it is easy to get a referral, and IVF on OMS really exists.
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