HYIP in "Nature"

What is behind the statement of a Russian scientist about genetic editing of embryos?

Alexey Aleksenko, Forbes, 11.06.2019

A few days ago, an article was published in Nature about the intentions of the Russian geneticist Denis Rebrikov to become the second scientist in the world, after He Jiankui, who will make heritable changes to the human genome. Forbes clarified what the researcher meant.

The article published on June 10 in the popular science section of Nature was published under the heading "Russian biologist plans new CRISPR-edited children". We are talking about Denis Rebrikov, Vice-rector for Scientific Work of the Pirogov Russian National Research University, cooperating with the Center of Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov.

According to the article, Rebrikov's research is essentially in line with experiments conducted last year by Chinese scientist He Jiankui, who genetically edited one of the embryo's genes (CCR5), which presumably was supposed to provide resistance to HIV. The experiment led to the birth of two healthy twin girls. These experiments were critically received by the scientific community: according to the general opinion, they did not meet ethical standards, since there was no clinical need for such genetic modification, and the CRISPR-Cas9 gene editing technology itself is not ready for use in humans, since its safety has not been proven.

Doubts about the ethical justification of such experiments, including the work of Rebrikov and his colleagues, were expressed by scientists to whom Nature turned for comments, including the inventor of the gene editing method Jennifer Dudna.

The immediate reason for this publication was probably a scientific paper published by Denis Rebrikov and his colleagues in the journal "Bulletin of the Russian State Medical University", in which they report on the successful and effective editing of the CCR5 gene in a human zygote (fertilized egg). In the scientific article itself, there is no indication that the researchers intend to transfer an embryo into a woman's uterus in the near future and in any way overstep the ethical standards adopted by the research community in this field of science. Thus, it remains unclear what the sensationalism of the article is and what doubts the scientific community has about the experiments conducted at the V. I. Kulakov TSAGIP. Forbes asked Denis Vladimirovich Rebrikov to answer a few questions.

– At what stage are your studies?

– We know how to make edited embryos, but we don't transfer them to women yet for two reasons. Firstly, we have not definitively proven the safety of this technology. We are working to correctly show the absence of changes in other parts of the genome – this is the main danger of using the method.

Secondly, we are looking for an adequate clinical model. So far, the only option for adequate use, if we talk about HIV resistance, is the case when a young HIV-positive woman responds poorly to antiretroviral therapy. Such cases are infrequent – one in several thousand patients. If she categorically refuses surrogacy and at the same time insists on realizing her reproductive function, this may be an indication. With the caveat that we have to get permission for such cases.

– Why do you think that you are closer to the finish line than other research groups?

Such experiments are being carried out in a huge number of countries, including the USA and the UK. And everywhere the question is whether to transfer the embryo into the uterus: they do not transfer, and we do not transfer, because it is impossible. But I think we are a little bit closer to success because we have a system security verification model. I have not heard or read anywhere that other laboratories have such a model as ours. In short: we compare the original genome of gamete donors with the genome of the edited embryo using a special bioinformatic approach.

– Where do oocytes (human eggs) come from for your experiments?

– Oocytes remain from standard in vitro fertilization (IVF). They are provided for scientific research by the patients themselves.

– Is it ethical to use donor oocytes for genetic editing of embryos without informing donors?

– If the patient does not object, he signs an informed consent for the use of his cells for scientific research. At the same time, we guarantee that there will be no transfer of the embryo into the woman's uterus.

– How do Russian laws regulate such research?

You can work with an embryo up to the age of 14 days without transferring it to a woman. This is an international rule, and Russia follows it.

– But you plan to move on to the work of transferring embryos into the uterus in the future. What changes in the law are needed for this?

– It is necessary to officially prescribe in the law that in clinically justified cases this is permissible. There is no consensus in the scientific world about what should be considered a clinically justified case (although there is a consensus that the case was not clinically justified in He Jiankui's experiments). But if clinical indications are prescribed in the law, then consensus is no longer required.

– Obviously, such a law cannot be developed without the participation of scientists?

– This is impossible without the participation of scientists, doctors and broad groups of the public. But, I repeat, there are cases against which no public will object: this is when we know for sure that 100% of the children of a given pair of parents will be born sick. I'm not even talking about HIV right now, but about other cases when the use of this technology will be even more justified.

– How long can this milestone be reached?

– I think that humanity in a broad sense will come to the legalization of editing the embryo genome within a few years. As for Russia, it's difficult to say here: we can suddenly rush faster than everyone else, or we can, on the contrary, slow down for a long time.

Other opinion

Ekaterina Pomerantseva, a geneticist and medical director of CGRM "Genetiko", shared her doubts with Forbes. In her opinion, "there is some discrepancy between the current noise and what is happening in reality. The scientific community was swayed by the idea of embryo transfer. The article says: "A Russian scientist says that he is going to produce genetically edited children and become the second in the world to do it." Work on reducing the number of off-target mutations, on the other hand, makes this project not the second in the world, but the three hundred and fifteenth since the end. It is obvious that many groups are working in this direction and their successes are significant. In Russia, too, it is quite possible to do this. But what does all this pathos have to do with "I think I'm crazy enough to do it" ("I think I'm crazy enough to do it")?"

Pomerantseva also comments on Rebrikov's statement that his research group is looking for an "adequate clinical model": "The suspicion that the statement for Nature was made for the sake of hype is strengthened when the researchers themselves admit that they have not yet managed to figure out how to use it all to solve clinical problems. There is an obvious goal – to help the birth of children in couples where one of the parents is a homozygous carrier of a dominant disease, and a severe one. I know one such example – about 100 people living in Venezuela in the area of Lake Maracaibo, where the frequency of Huntington's disease is high. I wonder if messengers from different world laboratories have appeared in this settlement yet, predatory prowling in search of a legitimate opportunity to apply this technology to people. I hope no one will stoop to offering money to the residents there so that they will portray a desire to give birth to a child with the help of genome editing."

"Why do we have to go so far for clinical models? Do we also have a lot of people with hereditary diseases? But the fact is that in almost any couple with a high risk of having a sick child, this risk is still not 100%, but either 50% – with dominant diseases such as Huntington's disease – or 25%, as with recessive, such as cystic fibrosis or SMA. In such pairs, genomic editing is not necessary – you just need to select healthy embryos during IVF. This procedure is called PGT, preimplantation genetic testing, and is widely used all over the world, including here."

"And this leads to the third question of the Kulakov Center's research," continues Pomerantseva. – Was the provision of germ cells voluntary, informed and free of charge? As oocytes, so, by the way, and sperm. It's one thing when a person gives up their cells in order to help infertile couples have children – I don't see any problem in this. Another thing is when the donation of gametes occurs for the sake of experiments with incomprehensible clinical value. It doesn't seem so justified to me. This is not even a question for the researchers themselves, but for the ethics committee that approved the experiment."

According to Pomerantseva, such sensational publications only hinder the development of technologies for the treatment of hereditary diseases: "The technology is not ready, there is no clinical model that does not cause complaints – so why? And do you know what the most offensive thing is? The technology will be "ready" very soon, but due to such hasty, hype publications, a complete ban on editing germline cells may be introduced. It will be very difficult to lift such a ban later, and all research will be interrupted for many years."

"And, to be honest, I am offended that this news exposes Russian science as an example of something dangerously uncontrolled. If there is no ban, then everything is allowed," Pomerantseva notes in conclusion. – And so there is a persistent myth about Russia that bears roam the streets with balalaika here and take away vodka from infants. So now these babies are also genetically modified."

Denis Rebrikov rejects suspicions that the HYPE was created intentionally: "This report was not my initiative, they turned to us themselves." He insists on the uniqueness of his approach to detecting the inappropriate activity of CRISPR-cas9, but generally agrees with Pomerantseva's main argument: "There are several – but not many – examples when genomic editing at the embryo level can be ethically justified."

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