Chinese scientist Jiankui He announced on Monday that the first genetically modified people in history are already living among us: we are talking about the birth of twin girls who, using CRISPR technology, have artificially altered the gene responsible for susceptibility to HIV. In this sensational story, a lot is still unclear. First of all, the author announced the experiment itself not in the generally accepted way - by means of a publication in a scientific journal, but in a video on YouTube.
The university where Jiankui He worked disowned the project, colleagues condemned the experimenter, and the Chinese authorities began an investigation. N + 1 asked scientists to tell how realistic the story told by a Chinese scientist looks like, how accessible is the method of genetic modification of human embryos, what risks and dangers can arise in such experiments, why such experiments are prohibited in most Western countries and whether we can wait in the near future genetically modified athletes, intellectuals or "service people".
What happened?
In short: Jiankui He of the Southern University of Science and Technology in Shenzhen CRISPR / Cas9 edited a zygote obtained by fertilizing a mother's egg with the sperm of an HIV-infected father (with undetectable viral load), modifying the CCR5 gene in it. This mutation makes a person less susceptible to the risk of contracting HIV. The embryo was then implanted to the mother using standard methods used in in vitro fertilization (IVF), and the result was twin girls, Lulu and Nana.
He states that another woman is now pregnant with a genetically modified child, and seven other couples are participating in the experiment, which is currently suspended "due to the current situation."
Why is He's results doubted?
Doubts arose because of the form in which the new result was announced. First, He did not publish his work in a scientific journal, violating the usual procedure for announcing the results of experiments. A journal article is usually read and evaluated by several reviewers and an editor prior to publication.
Instead, Hae recorded a video on YouTube, in which he announced not only success, but also that the girls who were born could not be seen, and the information about their family was classified. The Southern University, where the scientist is formally listed, added fuel to the fire - they said that he had been on unpaid leave for six months and they knew nothing about this work.
Secondly, there are doubts of a more general kind: why, the famous science journalist Leonid Schneider asks, was HIV chosen for such an epoch-making experiment, and not some fatal congenital genetic disease?
Paul Kalinichenko, a professor at the Kutafin Moscow State Law University (MSLA), who studies world practices of legislative regulation of genetic experiments, agrees with Schneider. “This is a very strange example. HIV is not a genetic disease, that is, editing the genome does not result in treatment, but only in reducing the risk of infection. But HIV is a very well-known disease. Because heart defects or hemophilia are rare, they do not excite people so much, many have not heard of them at all. You cannot create a sensation with them, but with HIV it is possible, it is a pandemic, a kind of tribune. Because of this, I doubted the veracity of [He's statements],”says Kalinichenko.
Is the birth of genetically modified people even possible?
Yes, quite - and most experts agree with the practical possibility of such work. Moreover, He is in one of the best locations for such research.
“It is difficult to verify what has been said, but in assessing a hypothetical possibility, we can rely on the history of previous years. And we know that Chinese scientists were the first to edit the genome of a human embryo - this experiment was carried out back in 2015. There it was about non-viable zygotes, that is, the embryo was not implanted in the mother. A year later, our famous compatriot Shukhrat Mitalipov, who now works at the Oregon University of Health and Sciences, developed and consolidated this experience, says Pavel Volchkov, head of the genomic engineering laboratory at the Moscow Institute of Physics and Technology (MIPT).
Mitalipov published his article in Nature according to all the canons. It proves the possibility of editing the human genome at the embryonic stage in order to avoid the manifestation of a genetic disease - hypertrophic cardiomyopathy, for which today there is only symptomatic treatment. The gene editing drug was injected into the zygote - an embryo at the stage of its unicellular development. The zygote was then allowed to develop into a blastocyst, the first multicellular stage. By analyzing the genome of the cells, it was shown that the editing took place. The experiment was interrupted at this point.
“As you can see, all the fundamental work was done, it only remained to transplant this blastocyst back to the mother - that is, to perform a completely routine operation, common in IVF, which is used by women, for example, with obstruction of the fallopian tubes. Why was the experiment always interrupted before? In order not to conduct an illegal experiment on humans. The fact is that experiments on embryos are legal, since in different countries he is not considered a person until a certain age. It was up to this age stipulated in the law that they raised the multicellular stage,”explains Volchkov.
How difficult is it?
Apparently, it is not very difficult to breed genetically modified people - of course, in the conditions of a modern laboratory engaged in genome editing and, preferably, working in a large reproductive clinic.
“The technology of microinjection into a fertilized zygote, with the help of which the genome is edited, is not difficult,” says Pavel Volchkov. - And He worked in a laboratory where IVF is done. In such a laboratory, there is always at hand a large number of fertilized eggs from parents who are trying to give birth - usually more eggs are taken for IVF than necessary, in case of failure, and they remain in the clinic. This means that there is always an opportunity to stab the tools of genetic editing into zygotes, let them develop to a certain stage and evaluate the effectiveness of this procedure."
“The technique consists of several procedures. Embryological procedures - embryo, zygote, micromanipulator, injection - can vary from laboratory to laboratory. He, at least according to him in the video, carried them out in the same way as we do in our work, says a geneticist, vice-rector of the Pirogov Russian National Research Medical University (RNRMU), head of the genome editing laboratory at the Kulakov Scientific Center Denis Rebrikov. Previously, a scientific group under his leadership conducted almost the same experiment with human embryos, with the only difference that the edited eggs were not implanted in the mother.
According to Rebrikov, this is a standard procedure for treating male infertility according to the ICSI (Intracellular Sperm Injection Protocol) protocol, which is used when the sperm are too immobile for conception: “Simultaneously with the sperm, we use a micromanipulator to introduce a mixture for gene editing into the egg, thus obtaining a zygote,”says the scientist.
“Standard commercial enzymes like Cas9 are usually used for editing. There are quite a lot of enzyme options today, so it cannot be said which enzyme He used. But the rest of the components of the reaction mixture: the guide RNA guiding the enzyme, oligonucleotides and a special “DNA patch” (a DNA fragment that acts as a template in the sewing process) - as a rule, each laboratory does it independently,”Rebrikov continues to explain.
The mutation that was introduced into the embryos is also not entirely new. Moreover, it is not artificial either - about one percent of Europeans are innately resistant to HIV, that is, they carry two alleles of this mutant gene, and 10 percent carry one allele.
“This modification corresponds to a variant of the gene present in the population, which is an evolutionary allele, a variant of a gene without 32 letters. And there is a kind of ethical relief in this, because we are not saying that we have created a new allele, a new variant of a gene that is not found in humans. Thousands of people were born in a completely natural way and live with just such a variant of the gene,”emphasizes Rebrikov.
How dangerous is it?
The technique has already been tested, but the transition from laboratory to clinical practice is a completely different matter, and it takes pharmaceutical companies years, if not decades, to do this. From a purely technical point of view, to ensure safety, you need to be sure of two things: the method effectively edits the target DNA region, and this happens on a statistically significant sample with a low percentage of refusals (editing of the target locus), and at the same time other parts of the genome are not edited (non-editing of a non-specific locus).
“Given the size of the center He worked with, this technique was likely to have been practiced for three to four years. We collected information on embryos and, based on our statistical data, allowed ourselves to conduct this kind of experiment,”Volchkov suggests.
Genetic therapy for HIV itself is not entirely new either. Songamo is testing this method to treat the virus, but only on somatic, “normal” cells, not embryonic stem cells. It has come to clinical trials, which means that a lot of data has been accumulated on the problem. This is both company data and open data in scientific publications.
“This gene and the targeting system are well studied, the Chinese did not do it blindly, they only transferred this technology to editing the embryo, not somatic cells,” notes Volchkov.
However, he is not sure of the 100% correctness of the procedure performed.
“What would I like to see to make sure it works correctly? First of all, these are preliminary experiments on cell lines (embryonic stem cells). A statistically significant number of experiments on embryos with interrupted development - say, 25-50 cases, where it is clearly shown that the target gene is being edited and there is no or almost no nonspecific targeting of other alleles that could make a negative contribution to the state of the future person. Only after that could we proceed to the next phase,”says Volchkov.
But, according to him, the question arises about the legal regulation of such experiments. “Only the regulator, in this case the Chinese equivalent of the FDA, can establish the criterion for this 'almost absent'. Until there is no criterion, it is difficult to reason about what is acceptable and what is unacceptable,”the scientist argues.
“But let's imagine that this stage has been passed. Next I would like to see tests on an animal model. The most closely related model to man is the great ape. If genetic editing was first demonstrated on them, and not on human twins, it would be more correct, - continues Volchkov. "Moreover, work in this area is already underway: this year, Chinese scientists published an article in Nautre that they cloned a macaque (non-human monkey), and another one that they edited its genome."
He and his group, on the other hand, do not seem to want to waste time experimenting with monkeys. “The fact that they skipped this important stage and moved on to experiments on humans is not in their favor,” concludes Volchkov.
At the same time, human embryogenesis is a highly self-regulating system, and if something goes wrong in it, then embryonic development is terminated (miscarriage occurs at one stage or another of pregnancy). However, this mechanism, unfortunately, does not always work, the scientist notes. But if you rely on the high probability of his work, this means that the very fact that girls are born confirms the intactness of their genome.
Professor of Skoltech and Rutgers University Konstantin Severinov notes that, strictly speaking, conclusions about safety can only be drawn by bringing the experiment to its logical conclusion: after genetic manipulation of the egg, a child must be born, mature, give birth to children of his own, live more or less normal a life. “So it was with Dolly the sheep. The success of the experiment with her, in particular, lay in the fact that she gave birth to another sheep. But in humans, the lifespan is comparable to that of researchers. In this sense, it is very difficult to set up an experiment to meet the level of evidence that one wants to have before using the procedure,”said the scientist.
Comparison of original and edited genetic code of Lulu and Nana / Sean Ryder.
Is it ethical?
Experts believe not. Moreover, for several reasons at once.
According to Oksana Moroz, associate professor of the Department of Cultural Studies and Social Communication of the Russian Academy of National Economy and Public Administration (RANEPA), there are two approaches that justify the morality of certain actions - deontology and consequentialism.
“Deontology proposes to make decisions about morality on the basis of the rules accepted in society. If we follow the rules, then we act morally, if not, then it is immoral. The whole story that experimenting with embryos and not destroying them after a certain period is an immoral act fits well into the deontological approach. Consequentialism evaluates the morality of an action through its result. If the consequences are good, useful, then this is good. And it is to this approach that the Chinese scientist appeals. It doesn't matter how he says that I proceeded from moral premises that are not accepted by everyone. It is important that the consequences of my actions will be wonderful,”explains Oksana Moroz.
But the question of global consequences in this case goes beyond concern for the health of specific people. We are talking about the integrity of the genetic base of the human population, the scientist notes.
“When we edit the genome and, as it were, construct a new person, we cannot be sure that we edited exactly what needed to be repaired and did not damage something else that is important in the long term. At first glance, there seems to be no harm from such manipulations, but since there are no longitudinal data, we cannot judge to what extent our intervention in the genome only helps to heal and does not cause any delayed harm. Indeed, in the future, these genetically modified people will fall into the volume of human genetic material, they will become parents themselves. And it is possible that our intrusion into the common genetic space may have a delayed effect,”notes Moroz.
In addition, there is also the issue of informed parental consent. He himself has already stated that the people he subjected to this experiment (the parents of the twins) knew what they were doing. But there are doubts on this score. “On paper, it was recorded that he was conducting an experiment on HIV therapy, and only orally did he tell his parents what he was planning to do. And the big question is, how far people far from genetics could understand the essence of his actions,”the scientist says.
The potential problem of elitism is also worrying.
“We can proceed from the assumption that we will cure everyone - even at the stage of embryonic development, when future people still do not feel anything and do not suffer. But if our technology is introduced and released to the market, then, most likely, it will not be available to everyone. And then some X-men will appear in society, a new type of inequality will arise - not social and not physiological, inherited from birth, but inequality based on artificially made physiology, - says Oksana Moroz. - And it is not very clear how we will cope with this, because we are already struggling to cope with the fact that there is gender diversity and the third sex. How prepared is society for characters with this type of character?
Finally, this is an experiment in humans.
“The scientist wants praise, but does not think that as a result of his actions, living people will appear who will think and feel and understand that they were born as a result of an experiment. This is a story about Frankenstein's monsters who are created, and then tormented by the fact that they are the fruit of human pride. Religious and moral factors are intertwined here, which call into question the legitimacy of such actions. It is no coincidence that Chinese institutions have distanced themselves from this work,”the expert notes.
However, Denis Rebrikov from the Russian National Research Medical University says that it is too early to think about the problem of the appearance of “supermen” as a result of genetic editing. So far, in all cases, the genetic modification of embryos has been limited only to those genetic variants that are already in the population. “We know that there are people with a deletion in the CCR5 gene, there are quite a few of them in Northern Europe, that this is not a mutation that entails serious consequences. No one is going to insert any letters into the human genome that do not exist in it,”he explained.
Rebrikov emphasizes that in such experiments, the genomes of both parents and the genome of the resulting embryo should be sequenced before its transfer to the future mother. In this case, you can be sure that only the planned DNA sections have been changed and no other genetic changes have occurred.
It is forbidden?
Here we turn to the deontological approach of ensuring morality.
“This is an area with poorly developed legal regulation. It accumulates around prohibitions and restrictions, but the rules of a procedural nature, allowing a positive solution to certain issues, are minimal,”said Paul Kalinichenko from Moscow State Law Academy.
That is why such experiments are more possible in the countries of Southeast Asia, where regulation in this area is weaker than in Europe or the United States. In Europe, ethical barriers are deeply rooted in legal practice, so the case under consideration falls into a broader category - “experiments on people”. They are strictly prohibited, and this is historically predetermined. “In Europe, this refers to eugenic research, and in the EU, eugenics is prohibited in general, even positive eugenics. Therefore, such work is impossible there,”the expert concludes.
Great Britain stands apart in this row. There, work on editing the genome of embryos was allowed in 2016, following China - of course, under the supervision of ethical and research committees.
“In the US, the situation is milder, but it does not mean that Americans can afford such experiments right now. There, the law differs from state to state, and still the legal regulation has not fully developed. In addition, the American approach is, let's say, practice-oriented. A certain gap in the legislation is laid specifically so as not to hinder the work of the industry where there is commercial potential. Full regulation is postponed until later: if something goes wrong, they will take care of it. In the meantime, everything is harmless, let it develop,”explains Kalinichenko.
This approach can be seen in the regulation of work with embryonic stem cells: restrictions apply only to research that receives federal funding.
“China is a non-legal state, therefore, the meaning and goals of the state's policy cannot be fully understood. It is utilitarian in its goals and objectives, that is, it submits to the tasks of the CCP. But what is important is that the Chinese authorities support scientific research, allocate huge amounts of money to outbid scientists and create conditions for their activities. Apparently, the result is important for them, and this may explain a certain liberalization of the legislation. That is, the indulgences that the Chinese make serve the purposes of science, not business. If it comes to clinical practice, the liberalization of laws can quickly be replaced by tough regulation, the scientist notes.
In Russia, regulation in this area has been lowered to the local level. Much here is determined on the basis of existing practice and norms of specific institutions, is not subject to any rigid circulars. The expert does not undertake to assess whether this is good or bad, but calls for the improvement of Russian legal reality based on an objective analysis of needs, including scientific work.
How soon will such operations become commonplace?
It doesn't seem to matter whether genetically edited babies are born right now. If this has not happened yet, then it can happen at any moment, and it will happen without fail.
“It is only a matter of time before this will be done. It doesn't matter if it is He or someone else. There is such an expression: it's not a question of if, but when, - "the question is not whether it will happen, the question is when it will happen." I think the person who does it first and succeeds will have a very difficult time at first. But then they will carry it on their hands,”concludes Konstantin Severinov.
Alexandra Borisova, Daria Spasskaya