Why Russians can't change their genes

The "Snob" asked Alexander Karabelsky from Biocad about how we can keep up with the progress in the field of gene therapy and gene editing .

The last month has brought a whole bunch of scientific sensations from the field of gene therapy. First, a seven-year-old boy grew a new skin from genetically edited cells. Secondly, for the first time, gene editing was carried out in the body of a living patient. Finally, several research groups in different parts of the world have learned to edit DNA with unprecedented accuracy, without cutting the chromosome, but only making the minimum necessary adjustments.

All these achievements have one thing in common. Someone will say that it is embarrassing to mention this, but we will still take a chance: all these brilliant scientific works were carried out without the participation of Russian scientists. Meanwhile, many respected and honored molecular biologists work in Russia. Last fall, many of them gathered at the BiotechClub conference organized by the company Biocad, and there, in particular, discussed the issues of gene therapy. The round table devoted to the problems of editing human genes, including ethical issues, was moderated by Alexander Karabelsky, PhD, Director of the Department of Advanced Research at Biocad.

The situation when genes are edited in the USA, Europe and China, and ethical conflicts are discussed in Russia, seemed to us worthy not only of an understanding smile, but also of a slightly deeper conversation. This is what we talked about with Alexander Karabelsky.

1. What's going on?

– Alexander, we are a little puzzled by the situation when scientists are worried about the ethical problems of research in which they have not yet succeeded too much.

– If we talk about gene therapy in general, there are quite a lot of developments in our country. If we are talking about gene editing, then CRISPR technology is widely used in laboratory research. As for the practical use, I am not aware of this. In the clinic, this technology is not used exactly, as for preclinical trials – most likely, yes, but such studies are usually closed.

– Where, for example, could this be done?

– There is, for example, the AGCT company, created on the basis of the R. M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology and the First St. Petersburg Medical Institute. The essence of the project is the editing of T–lymphocytes so that they lose the ability to become infected with HIV. This topic is not new: in the USA, the company Sangamo Therapeurics has been doing this for many years, but for some reason their product has not yet reached the market. As far as I understand, AGCT is trying to do something similar. They are residents of Skolkovo and have recently received a grant.

– But this is all, to put it mildly, quite far from implementation?

– If we talk about CRISPR, then most of the developments are quite far from being implemented everywhere in the world. But simpler techniques, such as replacement gene therapy, already look quite realistic.

– What is going on in this direction at the Biocad company itself?

– We have two main directions. They are both high-tech, and at the same time have a high chance of growing to the stage of a finished medicinal product in the next few years. The first direction is substitution therapy, when we take a severe hereditary disease, usually monogenic, and compensate for the missing gene by injecting it with a virus or nanoparticle. These are hemophilia, spinal muscular atrophy, Duchenne muscular dystrophy and, of course, eye pathologies, because the eye is a very convenient organ for this kind of therapy. Here we are at the stage of preclinical research: we have created a laboratory technology for obtaining recombinant viral vectors and are working to increase their effectiveness and remove side effects, we are already conducting experiments on animals.

The second direction is, of course, oncology and CAR – modification of immune cells to make them highly specific to the tumor antigen. We have already learned how to create modified cells, they really kill who they need, and now we are working to bring the technology to the stage of clinical trials faster, because patients need it very much.

– As for surgeons, in many countries this is already a clinical practice, children are treated with this. You are at the preclinical stage. This means a lag of at least five years. Don't you think it's much easier to introduce ready-made foreign techniques into the clinic than to start the whole story here from scratch?

– We already have all the technologies that are necessary to make a normal, high-quality product that will not be inferior to American analogues in any way. And there is a huge interest in these products from both clinics and the state.  

– Did I understand your remark correctly: your hope in this competition is state support and nothing else?

– No, a high–quality and affordable product will be in demand by the market - as it happens with the monoclonal antibody preparations that we already produce. On the other hand, it is not yet clear how foreign CART drugs will be supplied and sold to Russia, there are legal problems and there are problems with logistics. I do not exclude that they will come to our market even later than we release our product.

– "Bureaucracy and logistics" translates into simple language as "fools and roads": a fool will forbid everything, and a cart with a drug will get stuck in the mud.

– Biomedical cell products are a completely new field, and the rules governing their registration and use have only recently begun to be created. Everything concerning human health is regulated very strictly everywhere, and the rules should be the same for everyone. It's great that such rules are already being created, and they correspond to the best foreign practices. If we are lagging behind in this area, it is quite a bit. 

2. What is the paradox?

– Let's return to your panel discussion about the ethical aspects of gene editing. What have you come to?

– In fact, we didn't talk much about ethics. I have attended such round tables several times, and each time the conversation drifted to the same topic: if we introduce methods of early prenatal diagnosis, family planning, etc., the problem of genome editing will lose most of its relevance. Both for the world as a whole and for the state, it is much more profitable to simply plan and promote a healthy life than to try to fix something later. If you know that you have a predisposition to a hereditary disease, that you may have children with genetic abnormalities, then it is probably better to check everything in advance.

– That is, to terminate the pregnancy in case of an unfortunate combination of circumstances?

– No, no, let's not go that far. Let's imagine such a hypothetical situation that in our country all citizens have undergone genetic profiling, everyone knows their genetic risks. And if you want to have a child, then either you need a certain partner to reduce the chances of having a sick child, or, please, do artificial insemination with the possibility of selection. What is the point of taking risks and giving birth to a deliberately sick person?

– And this reasoning does not seem to you ethically dysfunctional?

– This is a difficult question, I'm generally afraid to get into ethics. It just seems to me that if there are technologies that can prevent this, why can't they be used?

– Look at the situation: the main locomotive of research on gene editing – as well as prenatal genetic diagnostics – is the USA. And this is a country where the majority of the population is sure that a person's life is sacred from the moment of conception. The arguments you have given are ethically unacceptable to most Americans. And here we are, in Russia, which has overtaken almost the whole world in the number of abortions and bought a couple of sequencers with a sin in half, we start talking about the fact that all this gene therapy is not so necessary if we necessarily conduct genetic screening of the population and do not go on about the dense prejudices. Do you agree that there is a paradox here?

– In fact, it is the USA that is one of the leaders in the field of genetic screening.

At the genome editing round table, which took place at the Festival of Youth and Students in Sochi, an interesting topic was discussed: it is planned to publish individual genetic profiles on Facebook, to make this data completely public. I don't know how it beats with their Baptist ideological mood of the general mass, but there everything goes to the fact that it will be possible to choose a partner or friend by profile in social networks.

And let's not forget that genetic screening can help reduce the incidence of some hereditary diseases, but the scope of gene therapy is much wider.

3. What to do?

– How many, in your opinion, on one-eighth of the land there are research groups capable of developing new genetic technologies?

– We have a lot of specialists who could work at the early stages of creating drugs. These are strictly fundamental studies, and they usually don't even have a goal to create the final product. Probably, no one else makes such products at this level now, except for us.

– So there are a lot of great molecular biologists working in the country, who write applications where it is written how it will be perfectly used in therapy, and then they defend their dissertations and go to America? No one even thinks about bringing this practical part of the application to something, do I understand you correctly?

– Someone leaves, someone stays to work. Fortunately, there are more opportunities for self-realization for molecular biologists, primarily in biotech companies. But the problems with the results of the activities of academic institutions being interesting to the industry, being in demand by it, of course, remain.

– How can this system be broken, how can it be straightened and made more natural?

– There's no way to break it. In the West, it is the same in academic science. But at the same time, every laboratory that has the potential to create a practical product has, as it is now called, an "industrial partner". And mechanisms to make interaction with him as effective and mutually beneficial as possible. We have many centers that are engaged in deep science and can create new technologies that will surpass all Western analogues, but, unfortunately, there are still few companies that can bring these technologies to the completion stage. We are one of such companies.

– You are another matter, you are a vertically integrated structure that leads the development from start to finish. And are there potential partners for academic or university laboratories who are ready to pick up this from the level of laboratory research and carry it further?

– There are very few of them. It's pretty sad here.

– So we don't have these potential industrial partners in principle as economic actors?

– There are many pharmaceutical companies in the country, but, as a rule, they have a different profile, all are engaged in drugs based on small molecules. And if some institute has similar developments, many can pick it up. But if we talk about biological preparations, new editing technologies, etc., then there are very few competencies.

– What do you think could be done to overcome the backlog? Maybe we should attract more venerable scientists from abroad, as is done in Southeast Asia?

– If there are normal conditions for life and work, everyone will come back by themselves, we have many examples in the company when this happens. Moreover, they return not even because of the conditions, but because of the opportunity to do interesting things that will definitely reach the product stage. If we talk about new technologies as such, then so far in our country there is no full-fledged legislative framework for them. So far, there are a number of unfinished points that do not even allow us to start clinical studies of cellular products. We also act as experts in the field of legislation on gene therapy drugs.

– How does this interaction with legislators take place?

– Since we are a leading company in our field in Russia, we are contacted by the Academy of Sciences, the Ministry of Health, the Ministry of Industry and Trade, and we are actively working with the government through expert councils and working groups. We have already done a lot in the field of biological drugs, our monoclonal antibody preparations are already being actively used, and this has significantly improved the drug supply of cancer patients in our country. In the West, such drugs are already the standard of therapy, but in our country they are only becoming the standard. And with new technologies, we are trying to do the same, but only even faster.

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