CRISPR — a tool for consumer eugenics?
What it is?
Recently, more and more one has to read a lot about the need to improve the properties of certain objects and subjects — from plants, in order to increase productivity and their resistance to droughts or diseases, and up to humans — in terms of enhancing our certain qualities (health, immunity, appearance, longevity ) What seemed like science fiction is today quite real projects with results. Here is one of these methods of improving properties that will be discussed beneath.
We owe our longevity to stem cells, which are located deep inside certain tissues of our body and replace instantly old cells. In recent years, science has made significant progress in the treatment of certain genetic diseases by editing the stem cell genome. To do this, scientists are first removing from the body, editing by making necessary changes in genome, and then place back into the patient’s body. This procedure is called CRISPR. CRISPR is one of the most promising technologies of recent years, and its role will only grow in the upcoming years. However, not everyone understands exactly how gene editing works, and a number of ethical issues arise. In short, CRISPR — more precisely, CRISPR / Cas9 — a powerful tool for editing genomes. It is based on an element of the bacterial defense system that biologists have adapted to modify the DNA of plants, animals, and even humans. The technology allows corrections in just a few days, not weeks or months. Human being has never had such an accurate tool for manipulating genes.
The history of CRISPR began in 1987 when Japanese scientists who studied Escherichia coli discovered unusual repeating sequences in its DNA. It was not possible to find out their biological significance, but soon similar fragments were found in the genome of other bacteria and archaea. The sequences are called CRISPR — Clustered Regular Interspaced Short Palindromic Repeats. Their function remained a mystery until 2007, when specialists in the Streptococcus bacterium, which is used to prepare fermented milk products, determined: these fragments are part of the bacteria’s immune system. The fact is that bacteria must constantly repel the attacks of viruses — their natural enemies. To do this, they produce special enzymes. Each time a bacterium succeeds in killing a virus, it cuts off the remains of its genetic material and stores them within the CRISPR sequences. This information is then used in the event of a new virus attack. When attacked, the bacterium produces Cas9 proteins that carry a fragment of the genetic material of the virus. If this site and the DNA of the attacking virus match, Cas9 cuts off the genetic material of the last and neutralizes the threat. For some time — this discovery was interesting only to microbiologists. However, everything changed in 2011, when biologists Jennifer Doudna and Emmanuel Charpentier decided to study the CRISPR mechanism more precisely. They found that the Cas9 protein can be tricked into giving artificial RNA. A protein carrying such RNA will look for genetic fragments that match what it carries. Having found a match with someone else’s DNA, it will begin to grind it, regardless of whether it belongs to a virus, plant or animal. As noted in a 2012 article by Doudna and Charpentier, this mechanism can be used to cut any genome in the right place.
In February 2013, it was proved that CRISPR / Cas9 can be used to edit DNA in mouse and human cell cultures. Moreover, it turned out that the technology allows not only removing unnecessary genes, but also inserting others in their place. To do this, just add enzymes that restore DNA. Scientists quickly realized the enormous prospects of CRISPR. If in 2011 only 100 articles about it were published, then in 2017 this figure reached more than 14,000.
The idea of gene modification is not new, and its various methods have existed for many years. However, CRISPR is superior to all previously known technologies due to its availability and accuracy. Editing a single gene will cost only $75 and take several hours. In addition, importantly, the technology works with any organism on Earth. There are almost infinite potential applications of technology. First, CRISPR allows scientists to figure out the function of various genes. It is enough just to cut out the studied gene from DNA and see what functions of the body were affected. However, the public is much more interested in practical applications. They can be divided into several points:
1) Changes in agriculture
CRISPR allows you to make crops more nutritious, tastier and more resistant to heat and stress. You can give plants other properties: for example, cut out the allergen gene from peanuts, and introduce resistance to the deadly fungus into bananas. The technology can also be used to edit the genome of domestic animals — for example, cows.
2) The fight against hereditary diseases
Scientists intend to use CRISPR to excise mutations in the human genome that are responsible for a variety of diseases, such as sickle cell anemia. The technology will also allow the excision of Huntington’s chorea genes or BRCA-1 and 2 mutations associated with breast and ovarian cancer. Theoretically, a CRISPR attack can even stop the development of HIV.
3) New antibiotics and antiviral drugs
Bacteria develop resistance to antibiotics, and developing new ones is expensive and difficult. CRISPR technology makes it possible to destroy certain types of bacteria with high accuracy, although a specific technique has yet to be developed. A number of researchers are also working on virus-targeted CRISPR systems.
4) Genetic drive
Using CRISPR, one can change not just the genome of an individual animal and plant, but also the entire gene pool. This concept is known as “genetic drive”. Usually, any organism transfers half of its genes to offspring. However, the use of CRISPR can increase the likelihood of gene transfer by inheritance to almost 100%. This will allow the desired character quickly spread throughout the population. In a more sparing version, mosquitoes can be made resistant to infection with malarial plasmodium. They will not be able to transmit the parasite to humans, and malaria will be put to an end. However, to implement such projects, it is necessary to overcome the doubts of skeptics who protest against such a large-scale invasion of nature.
5) The creation of “designer babies”
This possibility attracts the most public attention. However, according to scientists, so far our technological capabilities do not allow us to create children with desired qualities. For example, thousands of genes are responsible for the level of intelligence, and adjusting them all is not yet possible. Perhaps in the future technology will reach the desired level, but so far there is nothing to worry about.
In 2015, Chinese scientists attempted to correct the genome of a human embryo. They took a fertilized human egg with a spoiled gene leading to beta-thalassemia blood disease. Cas9 protein and RNA — guide were implemented into the cell, which were supposed to find and “bite” the wrong copy of the gene, followed by repair using a healthy matrix. As a result of the experiment, in 5–10% of embryos, the mutation responsible for the occurrence of the disease in adults was indeed corrected. It’s a good news.
The bad news is that all the cells of the treated embryos had a large number of mutations that did not appear at all where they were supposed. Thus, the technology needs to be improved, it is not accurate enough. Accurate editing is obtained when a portion of the target DNA with a length of a little more than 20 nucleotides complementary interacts with a completely corresponding RNA — guide. But there can be a large number of variants of the target sequence in the genome that differ from it by only one letter, even more variants that differ by two, and so on. Each of these variant targets interacts worse than a perfectly suitable target, say 10 times worse. However, since there are many such sequences, incorrect recognition (and, therefore, cutting and editing) is very difficult to avoid. How to deal with this is still unclear. Obviously, you need to improve the specificity of Cas9 protein and choose guides very carefully.
Not all scientists consider CRISPR a safe technology. For example, according to recent studies, gene editing can cause extensive non-targeted mutations. The authors of another work note that CRISPR is mistaken in 15% of cases.
Prospects to study CRISPR-systems
Today CRISPR is one of the most popular technologies. Many scientists and entrepreneurs dream of working with CRISPRs. Now these studies are becoming generally technological. There are few fundamental questions left. There are several established strong groups in the world, the competition is very strong. It is promising to do now what in 5–10 years can be hype, repeating the success of CRISPR/Cas. But where the next breakthrough will be, it is impossible to predict, this is the beauty of science. It is interesting that this yet unknown area of the future breakthrough should not at all be in the mainstream now. After all, 10 years ago, none of the “serious” scientists did CRISPRs. By the way, CRISPR/Cas is already the second case of how studies on the interaction of bacteria and their viruses lead to a revolution in biomedicine. The first revolution occurred in the 1970s, when restriction enzymes were discovered, without which molecular cloning and genetic engineering were impossible. Among the existing unresolved problems in the biology of CRISPR/Cas-systems, the following can be distinguished. We do not know where most spacers come from. After all, only a few percent of spacers are of viral origin, similar to DNA fragments of known viruses, all the rest, the vast majority, do not look like anything. An interesting question is the evolutionary origin of CRISPR/Cas systems. There is a hypothesis that they are related to transposons — DNA sections that encode special proteins that are busy rearranging those same DNA sections that encode them. Such unusual jumping genes. Now scientists are trying to confirm this hypothesis experimentally. In addition, the search for new, still unknown CRISPR / Cas-systems is quite relevant. Until recently, three different types were known, one of which, type II, turned out to be editable. Recently, scientists have experimentally confirmed the presence of three additional types of these systems, that is, people do not yet know all of their diversity. And among unknown systems there may be those that are promising from a practical point of view and free from the disadvantages of Cas9-based systems.
Another interesting goal of research, which has obvious practical interest, is to understand the molecular mechanism of target recognition and learn to control this process. This is a special case of the general problem of the specific interaction of macromolecules. Scientists do not understand very well how in cell molecules of proteins, nucleic acids find their “right” partners and avoid “wrong” interactions. Who helps cells make the right choice? CRISPR/Cas9 gene editing technology is uncomplicated, it is important to make sure that it is safe for humans, but in the future, it can democratize research in life sciences in general. Earlier media reported that for the first time it was possible to edit the human genome using CRISPR/Cas9 technology, which allows you to cut out certain sections of DNA that determine the body’s predisposition to certain diseases. A group of Chinese scientists introduced cells with a CRISPR/Cas9-edited genome into the body of a patient suffering from incurable lung cancer. In principle, this technology is effective and easy to apply. But there is only one serious problem: the human genome is very large, it is very difficult to ensure that you have edited only in the place where you need, and did not make any additional changes in other places in the genome. Cas9 is a bacterial protein that binds a small piece of the nucleic acid of the virus and, upon recognition, cleaves its corresponding DNA. It turned out that such a protein can be introduced into the cells of mammals, for example humans, and instead of a small portion of the nucleic acid that naturally originates from the virus, any other DNA fragment can be taken and it will induce the Cas9 protein (Cas9 protein itself is molecular “scissors”) to the site of your choice, actually programmed by you. Using CRISPR/Cas9 technology, one can make the Cas9 protein recognize virtually any place in the genome, break it, and then “fix” it. Imagine that in some place a mutation occurred, a change in one DNA base to another and due to which some kind of genetic disease arose. Therefore, using CRISPR/Cas9 technology, one can recognize this changed place, and then replace it with the correct one, that is, edit the genome. In terms of practical application in humans, it is still very early to speak, since clinical trials are ongoing. Chinese scientists took immune cells from several patients who had small cell lung cancer, and then the genome of these cells in the laboratory was changed using CRISPR/Cas9 technology to make these cells more active in terms of recognition of cancer cells. Then the edited cells were propagated in laboratory conditions. Now, each patient will be injected several times with his own edited cells, and for several months, they will see if it is harmful, because such hyperactive immune cells can lead to undesirable consequences. Patients will not be cured, now they are just checking that they will not get worse: safety tests. Similar clinical trials will begin soon in the United States. Scientists believe that for some types of cancer, but not for everyone, the technology will work. Within two years, you can wait for experiments on volunteers already with treatment. ”CRISPR/Cas technologies are rapidly developing and commercializing in the USA, China and Western Europe. You need to understand that, in principle, this is a simple technology, you can edit genes in your “garage”, you just need to know what you are doing and why. In the near future, this technology will make it possible to very democratize research in the life sciences and make it more accessible.
Problems, threats, CRISPR moral and ethical standards
Potential applications of the new technology include the treatment of hereditary diseases (hemophilia, beta-thalassemia, and muscular dystrophy), therapy of oncology and viral infections, including HIV. But there are more exotic potential uses. For example, the fight against multifactorial diseases (diabetes, schizophrenia, etc.) or editing embryos with artificial insemination to select a specific appearance for children. It is here that many ethical issues arise, which began to be discussed, but so far have not received a consensus solution from the world community. When is it possible and when is it impossible to apply genome editing? So far, in the absence of a single position among humankind, each country decides this in its own way. New genome editing technology can give wealthy parents the opportunity to pre-buy their inborn (and inherited) physical and intellectual benefits for their future children, which will equate them with divine providence. American biochemist Jennifer Doudna, one of the authors of the method, is already comparing her innovation with the atomic bomb. In both cases, we released forces that are very difficult to control and that are potentially capable of destroying humanity — or changing it beyond recognition. Today, she is an opponent of this technology and understands what its total implementation can lead to. Unprecedentedly accurate and at the same time relatively simple genome editing technology, probably opens the way to healing from many terrible diseases, from which there was still no protection. But at the same time, any ill-considered introduction of inherited changes in the human genome can lead to no less terrible consequences and jeopardize the very existence of our species. One of the ethical issues associated with CRISPR-Cas9 relates to issues of social justice — how this technology will affect society.
Or here’s another example of an opinion against. One of the creators of CRISPR/Cas genome editing technology, Feng Zhang, called for a global moratorium on the implantation of edited embryos and the birth of such children after a Chinese scientist reported the first successful experiment in this area. Chinese scientist Jiankui He announced the birth of the world’s first children from genetically edited embryos. According to the scientist, twins were born in whom he tried to create resistance to HIV infection by disabling the CCR5 gene. Although human cloning is prohibited in China, there is no direct ban on the genetic editing and implantation of viable embryos, unlike in the United States. The moratorium, according to Zhang, should act until the scientific community has developed safety protocols for such experiments. Based on the two views of the pioneers of genetic modification — Genetic modification for reproductive purposes would jeopardize universal human rights. However, there will be even more ethical issues related to new technologies in the field of genetics and reproduction in the future. Bioethics is becoming an increasingly important discipline.
Other problems are related to the fact that the possibilities of genetic editing change the very concept of a family. With the advent of artificial insemination and surrogacy, in principle, the understanding of the institution of the family has become more complicated. Now, some children, in addition to their father, may have two mothers: surrogate and “legal”. And if an egg is used for conception and a sperm pair, which are then transferred to a surrogate mother, the child also has two mothers — a genetic and a surrogate. Theoretically, situations are possible when a legal, genetic, and surrogate mother is three different people. Another problem is the emergence and development of Biomedical Offshores. People go to countries with loyal legislation to implement procedures that are ambiguous in terms of ethics and admissibility by the legislation of a particular country. Gene therapy is already becoming at the center of such “controversial” cases. In general, now, the world community is very careful about editing the genome, when it is not directly related to the treatment of serious diseases that cannot be cured otherwise. The fact is that technologies are still imperfect and not as specific as possible. So, in the mentioned experiment of Chinese scientists on embryos in the DNA of many embryos, not only the sites that the scientists planned to change, but also other, random ones, changed.
And here we come to a more global problem of ethical character — gene modification for reproductive purposes threatens the rights of people of future generations. Editing the genome for human reproduction is fraught with huge social risks. Potentially, it could threaten the health and autonomy of future generations, exacerbate existing social inequalities and lay the foundation for new market eugenics that will exacerbate discrimination and conflict. It is now actively debated whether such risks are acceptable, however, such discussions are conducted mainly in publications and at meetings of scientific and professional organizations, far from the eyes of the general public and the attention of civil society. It is important that the views of human rights defenders be heard during this debate. Imagine a world where rich parents will be able to buy genetic improvements that will give their children real or perceived benefits, where the future of children will be considered predetermined by their genes, where at birth they will be divided into “good” and “bad” depending on their DNA. How will this affect human rights and the right of children to determine their future? Gene modification for human reproduction consists in changing the DNA of human embryos. It differs from genetic editing for the treatment of diseases. Editing the somatic cell genome, or gene therapy, aims at treating living patients, while editing the embryo genome is not a cure. The result of the last will be a new human being with predetermined genetic characteristics that will be inherited by his descendants — and this is a serious moral and ethical challenge to human evolution. Gene therapy, if it becomes a safe, effective and widely available method, will be a great addition to the arsenal of modern medicine. Germ line editing, by contrast, does not heal anyone. It creates future children, depriving them of future generations of choice, whether to accept the modification of their DNA. In cases where there is a risk of transmission of a serious genetic mutation, existing embryonic screening techniques in almost all cases can eliminate unwanted genetic variation from the family line. Of course, during embryonic screening, important ethical questions are raised about which diseases are “unworthy of life”. But this procedure is much safer and less fraught with social and ethical complications than manipulations with human germ lines.
At the end of the 20th century, academia, politics, and pop culture first embraced concerns about editing human embryos. The 1997 Gattaka dystopian film talked about a brutal society where genetically advanced people take advantage of unperfected ones. The press resonated the words of molecular biologist from Princeton University Lee Silver about a genetically stratified society. He predicted that “the wide gap that exists between rich and poor nations will continue to deepen and deepen until, finally, their common human inheritance disappears”. In the same period, due to concerns about security, respect for human rights, and the potential emergence of high-tech with consumer eugenics, more than 40 countries have banned the modification of genes transmitted through generations. Several important international agreements in the field of human rights have also appeared, in which it is argued that the modification of germ lines in humans encroaches on human dignity, and yet this concept is basic to human rights:
• These include the Council of Europe Convention on Human Rights and Biomedicine, 1997 (the so-called Oviedo Convention). Its article 13 expressly prohibits interventions aimed at “changing the genome of the heirs of a given person”.
• Another 1997 document, the UNESCO Universal Declaration on the Human Genome and Human Rights, states that “the human genome underlies the original community of all members of the human race, as well as the recognition of their inherent dignity and diversity.” Article 24 states that “effects on offspring” may turn out to be practices “incompatible with human dignity”.
One of the important motives for the appearance of the Universal Declaration of Human Rights was the horror that humanity experienced before the Nazi eugenic crimes during the Second World War. Meanwhile, the same logic is behind consumer eugenics, which will arise if the modification of the germ line is allowed: a person will have little chance of breaking through his life if his unmodified genes are considered second-rate from birth. Such a prospect should especially concern human rights activists in light of the fact that recently there have been attempts to move away from the old position, when editing human embryos was considered unacceptable in the world. So, in a report prepared in 2017 by a committee of the National Academy of Sciences and the National Academy of Medicine of the United States, it was recommended to allow, under certain conditions, gene modifications for the purpose of human reproduction, which leaves an opportunity to expand such conditions in the future. However, in the real world, with its market pressure and inadequate regulation, these restrictions will soon crack. One has only to open the door for the modification of germ lines in people — and the spread and application of this technology will be impossible to curb. Pandora’s box is no longer close. Although, on the other hand, if there is a chance for improvement, and all people equally will get health without harm, then why not? But we understand the world in which we live in around — a world of libertarian chaos, justifying itself by market necessity. Therefore, on the horizon of the future CRISPR is an instrument of social inequality.
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Sergey Golubev (Сергей Голубев)
EU structural funds, ICO/STO/IEO projects, NGO & investment projects, project management, comprehensive support for business