Edit or wait?
Crack the code of Nature
Anastasia Penzina, "Scientific Russia"
In November of this year, the IV National Congress on Regenerative Medicine was held in Moscow. Every year, the event gathers leading medical specialists who exchange experience in various fields of science - from cell and gene therapy to tissue engineering. While big data and artificial intelligence are changing practical medicine, as well as forming new methods of treatment, regenerative medicine is aimed at replacing and rejuvenating our physical body. But there is a much more ambiguous direction of modern medicine – editing of the human genome. And the question of the possibility of its use in humans has become the main dispute on the scientific agenda. The Chinese scientist He Jiankui added fuel to the fire, who announced that he had conducted an experiment on editing the genome of human embryos. At that time, work on human material "in vitro" was no longer a sensation. However, he admitted that his team went further – the embryos with the altered genome were not destroyed, as in previous experiments, but planted in a woman. As a result, the first genetically modified people were born - the twins Lulu and Nana. The results of the experiment caused a large–scale discussion about the permissibility of such experiments from an ethical point of view, and also confirmed the opinion of many scientists - the effectiveness of editing technology is still far from ideal. At the Congress, we managed to talk with Maxim Karagyaur, a senior researcher at the Institute of Regenerative Medicine of the Moscow State University Medical Center. We tried to figure out what is dangerous about the desire to save people from incurable diseases, who should regulate this field of science and where it is striving today.
– Last year, a professor from China announced that he had managed to edit the human genome and create genetically modified children. The scientist said that thanks to the intervention of geneticists, girls are not susceptible to HIV infection. What do you think about this experiment, how successful it was, and what does it mean for the scientific community?
– The results of the experiment, as well as the fact of its conduct, came as a surprise to the scientific community. No one could have imagined that technologies that have not passed a full security check would be used so soon to edit the human genome. The girls who were born, indeed, received some resistance to the human immunodeficiency virus. However, Professor He Jiankui did not have the technical ability to conduct the experiment correctly and obtain the required mutation. He used one of the simplest modifications of genome editing technology.
The fact is that the efficiency of editing and the final result are largely determined by the genome repair system – the natural function of cells, the ability to correct chemical damage and breaks in DNA molecules. Since this process is mostly random, the restoration of the DNA structure in this experiment happened by chance. I myself saw an article with the results of sequencing the genome of these girls, and I can say that the editing did not go exactly as Professor He Jiankui himself expected: out of four alleles, 3 turned out to be modified, and none of them corresponded to the CCR5 delta32 mutation (that is, the chromosomal rearrangement of 32 base pairs in the CCR5 gene, which leads to to the immunity of its carrier to HIV – approx. HP).
There is another, ethical, side of the issue: the professor took responsibility for the fate and health of these girls. But to date, little is known about how the genome works, how it functions, and how genes interact with each other. Therefore, thoughtless interference with the genome can lead to a violation of its stability.
Before performing such an intervention, it is necessary to conduct a long-term comprehensive safety study in vitro, in vivo on various animal species, including primates, and only then on human embryos. All such procedures, especially at first, should be carried out strictly in accordance with international requirements and standards under the supervision of international institutions.
– How does the scientific community feel about editing the human genome, including from an ethical point of view?
– Each question has its pros and cons. On the one hand, I want to save unborn children from hereditary diseases from which they will suffer all their lives. Many scientists consider genome editing as a necessary operation to save a person from an incurable disease. On the other hand, there is already a wide range of reproductive technologies – perinatal screening, in vitro fertilization – that have a much greater degree of safety.
It is impossible not to mention another important aspect of genome editing technologies. To date, it is still not proven whether genome editing technologies are absolutely safe. The fact is that they lead to the splitting of DNA chains. And this, in turn, can lead to undesirable deletion (removal of an entire DNA fragment) or chromosomal recombination. Therefore, each case of editing, especially for therapeutic purposes, requires careful monitoring and study.
The active use of these technologies for heritable editing of the human genome can lead to abuse in order to improve human nature, which will entail the inequality that humanity has been struggling with for the last two hundred years.
– Are there international ethical standards governing the technology of genome editing?
– Unfortunately, today there are no international legal and ethical standards in the field of genome editing technologies that would be universal for each country. While these norms are in development, well-known scientists (Jennifer Doudna, George Church, Feng Zhang, etc.) are calling for a moratorium on heritable editing of the human genome, especially after Professor He Jiankui's statement.
It is worth saying that the professor promised to provide data confirming the safety of the modification in the near future. However, as far as I know, these results have not yet been obtained.
That is why it is necessary to create international ethical and legal norms for the control of genome editing technology as soon as possible. After all, the technology itself is simple. Therefore, it can be used in a wide range of countries, including those that are not developed from a technical and legal point of view.
The recommendations of the International Society for Stem Cell Research (ISSCR) and the International Medical Association (WMA) can become the basis for the formulation of such norms.
– As far as I understand, it all starts with animal testing. How do these tests allow us to work with the human genome in the future?
– Of course, the genomes of all living organisms are similar, and when working with the genome, the already mentioned DNA repair system is involved. The essence of genome editing technologies is to precisely cut DNA. And it is restored thanks to reparations. This recovery system has evolved and is common to all organisms. Therefore, animal testing is certainly an important stage for assessing the safety and effectiveness of genome editing technologies.
To date, there are two main directions of editing the human genome – somatic and inherited. Somatic cells – skin or blood cells - are widely used in clinical practice. Editing these cells allows you to cure certain diseases – pathologies of erythrocytes and leukocytes, epithelial cells and fibroblasts of the skin. Also, this method allows for the modification of stem cells of patients with HIV to make populations of sensitive cells (CD4+ lymphocytes) resistant to HIV infection.
– Is it possible to predict the consequences of interference in the structure of DNA now?
– The genome editing system was first used on bacteria. Its purpose was to destroy viral DNA within the small genome. The bacterial genome is thousands of times smaller than the human genome. Therefore, the probability that unique combinations of nucleotides will be repeated in it is very small. But when scientists tried to translate this technology for editing the human genome, they faced a problem: the sequence of 20 nucleotides, which most often becomes a target, is not unique in the genome. Such sequences, taking into account the replacement of one or more nucleotides, can occur repeatedly in the genome. This makes it difficult to modify specific DNA loci (Locus (Lat. locus – place) in genetics means the location of a certain gene on the genetic or cytological map of the chromosome. A variant of the DNA sequence at a particular locus is called an allele. An ordered list of loci for a genome is called a genetic map. – note NR).
In addition, our genome is a dynamic structure. During the process of genome modification, DNA doubling continues, the reading of matrix RNAs that will become the basis for proteins. There are also a large number of DNA breaks that are formed as a result of the unwinding of DNA chains in the process of doubling or synthesis. All these breaks occur randomly in different regions of the genome. And if at this moment editing begins in the area near the gap, then there is a high probability of deletion of an entire fragment of DNA or chromosomal recombination.
– When they talk about genome editing, personalized medicine is often mentioned. How related are these concepts?
– These concepts are really connected. So far, genome editing is limited, but in the future, perhaps, this technology will be able to correct individual mutations of specific people, families or a particular population. It is known that the same diseases, for example, amyotrophic lateral sclerosis, Parkinson's disease and others, are associated with a wide range of mutations. And the genome editing technology will allow in the future to apply an individual approach to correct each of these mutations.
– Tell us, what are you working on?
– We started working with genome editing technology in 2014. Our team started research using this technology one of the first in Russia. We use the technology to study the function of individual proteins in the pathogenesis of various diseases. In particular, we have created cellular models that allow us to study the functions of individual molecules involved in the processes of atherosclerosis, fibrosis and liver repair, nerve regeneration and angiogenesis. Using these models, we were able to find out that blood vessels and nerves use similar navigation systems.
– The National Congress on Regenerative Medicine is taking place right now. How important do you think this event is for specialists?
– The Congress is certainly a significant event, especially for young scientists. They have the opportunity to hear the reports of world-class scientists. A young specialist understands how scientific research is built, what is its logic, how scientific thought moves from the primary theory to the final results. On the other hand, young scientists can present their work, exchange ideas and experience, establish interlaboratory connections.
– Tell us more about the project supported by the RFBR grant that you are currently working on?
– In addition to studying the technology of genome editing, I continue to study the influence of various neurotrophic factors on the restoration of nervous tissue. Initially, we studied the effect of these factors on the recovery of the peripheral nerve after injury. As it turned out, he is really recovering effectively. Based on these data, a gene therapy drug was created, which has successfully passed the second stage of clinical trials today. After a single injection of the drug into the human body, improvements were observed for a month.
The grant project continues research on this topic and is devoted to the study of the influence of genetic design on the recovery of the brain after a stroke. One of the factors of the pathogenesis of this disease is the release of blood from the vessels due to rupture. Blood enters the brain tissue: it has a toxic effect on nerve cells and causes inflammation.
The aim of the study was to evaluate the effectiveness of a gene therapy drug for reducing symptoms and effective recovery after a stroke. Preliminary data suggest that one of the forms of the drug may become a promising drug. The results of tests on rats showed that the introduction of this neurotrophic factor stimulates the recovery of the brain after a stroke, protects nerve cells from death and prevents the development of inflammation. Magnetic resonance imaging data (the "gold standard" in the diagnosis of strokes) also demonstrated a 10-fold reduction in the lesion compared to the control group.
– Let's sum up a certain result. When will genome editing technology be safe and will be used for therapeutic purposes?
– First of all, it is necessary to formulate laws, as well as create special institutions that control the use of these technologies. As for inherited genome editing, I find it difficult to answer here. Of course, editing inherited mutations is an important direction, but there are too many questions about it because of the possible negative consequences for humans and society.
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