Russian geneticist meets the challenges of his plan to make gene-modified babies | Science

By Jon CohenJune 13, 2019, 5:55 pm

Boldly rejecting the widespread sentiment – and regulation in many countries – that no one should alter the genome of a human embryo and transfer it to a woman, the Russian geneticist Denis Rebrikov publicly announced last week his intention to become the second researcher to cross this red line. "We can not stop progress with words on paper," said Rebrikov ScienceInsider yesterday, asked about international efforts to ban such research.

Rebrikov, who is at the National Research Center for Obstetrics, Gynecology and Perinatology of Kulakov in Moscow, has not yet received permission from Russia to carry out this experiment. But like Nature reported on June 10, he would like to use the CRISPR genome editor to change the CCR5 gene in embryos so that they are highly resistant to HIV infection.

This is the strategy that Chinese researcher He Jiankui attempted as part of a largely doomed experiment that led to the birth of binoculars. Jiankui, who did not publicly discuss his trial until the news revealed the details in November 2018, triggered an international push to strengthen surveillance of the human embryo studies. create hereditary DNA modifications. Concerns about this so-called "germ line edition" have led some leading scientists to call for a moratorium. A committee of experts from the World Health Organization and, separately, an international commission organized by academies of science have been convened to tackle the thorny question of how to create a framework for transferring responsible for editing the germ line from the laboratory to the clinic.

Rebrikov, whose laboratory is in a busy IVF clinic, does not plan to repeat the experiment. He thinks his design is defective. In his study, the Chinese researcher selected couples seeking IVF whose man was infected with HIV. Although this in itself does not pose much risk for an IVF baby (the virus can be washed sperm before injecting it into an egg), he stated that he wished to "vaccinate genetically" children against the future risk of infection with the AIDS virus so that they would not suffer from the stigma and discrimination their fathers infected with HIV were facing.

Rebrikov, on the contrary, wants to find HIV-infected women who have had a "poor response to antiretroviral therapy", as he explains in an article he published last year in the Bulletin of the Russian State University of Medicine (where he works too). The short article describes his preclinical work using CRISPR and its Cas9 enzyme to modify CCR5 in non-viable human embryos.

Rebrikov spoke with ScienceInitiated yesterday about his plans, addressing the scientific arguments against his CCR5 target and details of its ultimate goals and the perspective of its controversial experience. This is a condensed version of the conversation that has been modified for clarity.

Q: In your article, you cite two studies of HIV-infected pregnant women who do not respond to antiretrovirals (ARVs). These are two older studies with suboptimal drugs, and women have started treatment during pregnancy, which is not ideal. What current evidence exists that there are pregnant and infected women who fail all ARVs and pass them on to their babies?

A: About 30,000 to 40,000 HIV-positive women do not respond to antiretroviral therapy. They are like multi-resistant people. We use different therapies and HIV in the blood persists at a relatively high level. Nobody knows why. So, this young woman who wants to get pregnant has a high risk of vertical transmission of the virus to the embryo. This is the target group.

Q: Russia has about 1 million infected people. Would that mean you're talking about 30 women in the country?

A: Yes.

Q: Only a part of them wish to become pregnant. In addition, new antiretrovirals have been introduced regularly and the new integrase inhibitors have very little evidence of drug resistance. From there, what is the reason?

A: CCR5 the edition is only a proof of concept. If I can not find an HIV-infected woman who does not respond to antiretroviral therapy and wants to become pregnant, I will look for different cases where both parents have a homozygous mutation for a genetic disease, such as dwarfism, deafness or blindness. We need models to start using the CRISPR embryo edition in clinical practice. I think we need 50, maybe 100, cases of using that technology, and then we can use it more widely. For example, we can see in a family that all babies will be born with a high risk of cancer. Now, when genome editing is just beginning, it's dangerous and unproven, so we can not use it with them. But in the near future, I think we can tell these parents, "Would you like to make some changes to your baby's genome to reduce their risk of cancer?" And not just cancer, but different illnesses like cancer. Alzheimer's, Parkinson's disease, etc.

Q: But if we go back to HIV, even if a mother does not receive any treatment, transmission in utero or at birth occurs only about 15% of the time. Caesarean section further reduces the risk. You can also reduce the risk by giving the newborn a liquid dose of ARV. CRISPR, on the other hand, could alter the genome in the wrong place, causing a dangerous off-target mutation. Some studies suggest disability CCR5 make people more susceptible to other diseases like West Nile or even reduce their life expectancy. How do you balance this risk / reward equation?

A: My experience is focused on creating a genome editing system that has no untargeted activity. If we can convincingly demonstrate that there is no untargeted activity in the genome, this system can be used in different types of genome editing. I may have a unique system, and maybe that's only possible in Russia. I do not know. Is it worthwhile to prevent some transmission of HIV at the risk of reducing longevity or putting people at risk for other diseases? It's a philosophical question. Nobody knows the exact answer. It depends on many factors.

Q: Another risk is that you can only test a small percentage of the modified cells of an embryo before implanting it. [Embryos are sometimes “mosaic,” with different mutations in different cells.] Off-target changes may not be detected.

A: Yes, the main problem is mosaicism, because I can only take five or seven cells out of the 250 cells of the blastocyst. So we always have the risk of checking these five cells and seeing that everything is perfect and then we have problems in the other 200 cells.

Q: In the Nature article, you said that you could get an approval in a few months to a few years. How does the approval process in Russia work? And what are the laws and regulations regarding germ line modification?

A: Government approval is not the biggest problem, it's not the bottleneck. For me, the bottleneck is to find the right clinical model. If I find the right case, I think we can get regulatory approval.

Q: Suppose you found that the HIV-positive woman who did not respond to any antiretroviral wanted to get pregnant and was willing to do so. How long will the approval process take?

A: Maybe a few months.

Q: Have you discussed this with the regulators?

A: We have just started discussing it and they say that if the clinical case is good, we can discuss it further.

Q: In the United States and many other countries, there are laws that prohibit germ line modification. Is there such a law in Russia?

A: As far as I know, we have no direct restrictions on such experiences, but Russia generally subscribes to international rules. I know that the transmission of germ-line-modified embryos to women is prohibited in most European countries. In Russian law, we do not have that language.

Q: So you could face international laws that prohibit you from doing what you want to do?

A: I am not a lawyer. So, I do not have an answer.

Q: Two international committees are now discussing the process for germ line modification, and we also know the reaction to what He Jiankui has done. If Russia acted now with this experience, would these international considerations come into play?

A: I do not think it's possible to limit certain experiences around the world. You can try to limit it in certain areas, researchers can settle in islands in the Pacific Ocean if they wish. We can not stop moving forward with words on paper. So, even if we say, do not do nuclear physics because it can make a bomb, many scientists will do it anyway. We can not stop it. Many groups will try to experiment with embryos to transfer them to women, and maybe it will not be in my group, but we will see in the years to come that they will have results and that they will publish. This may be the problem for humans on the planet, that we can not stop progress.

Q: What does your clinic look like?

A: My laboratory is located in one of the largest centers of obstetrics and gynecology in Russia and has about 10,000 IVF cycles per year.

Q: What do you think of the harsh reaction to what he did?

A: It is a normal reaction of the human population and all life systems, not just humans – perhaps birds. Whatever the life system, 90% of the population is very conservative. It's normal. And maybe 5% is progressive. We just have to wait a bit, maybe a few years. And we need very good clinical cases to show people that this instrumentation is powerful, but it is safe and gives good results.

Q: Do you think that he was treated too harshly?

A: In Russia, we say that if you are successful, you are right. So, if he is a lucky guy and these girls are fine, in a few years he will be seen again as a good researcher.

Q: What was your reaction when you learned what he had done?

A: It was positive. In fact, I do not want to be the first. I want to transfer this technology into practice and its experience brings it closer to practice.

Q: Do you expect that if you go forward too, you will be intensely criticized?

A: In Russia, I do not think so much. Internationally? I do not want to go ahead until the ethics committees and the regulators have given us their approval. I think it will not be as crazy as his steps.

Q: Has something happened since the Nature story appeared? Did a government official call you to say, "Stop it, do not talk about it?"

A: I think Russia is a good country to do this type of experiment. It's not very free in politics, but in science.

Q: What do you think of germline modification that is not a disease, but an improvement in speed, IQ, or eye color?

A: This will be the next step. But in 20 to 30 years. Now, I'm against it. In 2040, I will support him. I am not against the idea itself. And these people who are opposed want to to have all these things in their children, but only by "divine providence," not by science. They are liars or stupid.