Why is it impossible to create a superman?
What genetic engineering can and cannot do
Konstantin Severinov, Post-science
Why do microbiologists need genetic engineering?
Genetic engineering is a set of technologies that allow you to directly change the genes themselves or their activity, transfer genes from one context to another, etc. The basis of modern genetic engineering is recombinant DNA methods that appeared in the mid-70s.
Genetic engineering is widely used in pharmacology. For example, human insulin, a hormone used to treat diabetes, is produced using such technologies. To do this, the human insulin gene is placed in the cell of the producing organism. At first, bacteria were used as producer cells, then they switched to yeast cells. You can also use plant cells. In all cases, the resulting cells, which did not exist in nature, produce the hormone in large quantities, it is isolated, purified and sold.
Monoclonal therapeutic antibodies used to treat cancer, such as rituximab [1] and bevacizumab [2], are also produced using genetic engineering – genes encoding specially selected antibody proteins are injected into mammalian cells. The resulting cells are used as factories for the production of targeted antibodies. In the microbiological industry, a giant market is based on genetically modified strains of bacteria: food additives, amino acids, antibiotics, and so on.
Many vaccines, such as the Russian vaccine against the coronavirus Sputnik-V, are also made by genetic engineering manipulations. In this case, the "thorn" gene of the coronavirus is introduced into the genome of a harmless adenovirus, and such a "pull-push" is obtained – a design that did not exist before in nature, where the adenovirus is, as biologists say, a "vector", a carrier of a "payload" – in this case, the genetic information necessary for the synthesis of S-protein coronavirus, an antigen to which antibodies should be developed that will protect us from coronavirus infection in the future.
Human cells are also used in genetic engineering. At the same time, we are not talking about the direct change of human cells in the body. Instead, human cells are used as devices to which you can add something else, some other gene. It turns out, in fact, new cells that did not exist before, and they will produce the products you are interested in or will allow you to better understand how our cells and individual genes are arranged and how they work. In laboratories, there are a large number of cell cultures taken once from people, many of whom have already died. For example, the popular culture that scientists work with is called "HeLa" – it was obtained from the endometrium of an African-American woman named Henrietta Lacks, who lived in the 20s of the last century. These cells are cancerous, so they are immortal and are used all over the world.
Genetic engineering does not always mean working only with cells. For example, you can introduce a pest resistance gene (usually a bacterium gene) into the cells of some agriculturally important plant. And then from such a cell you can get a whole plant, all the cells of which will contain the introduced gene. The descendants of this plant will also contain the introduced gene. Such plants can retain all their consumer qualities, but they will not require constant watering with pesticides, because the product of a new gene makes them toxic to insect pests.
How to diagnose diseases using genetic engineering?
If we have a technology that helps to "cut" and "insert" sections of DNA into the right places of the genome, then with its help we can not only create something new, but also better understand how specific genes work. To do this, for example, you can turn off some gene and see what happens to the cell after that. Geneticists work in this sense like little children left unattended in a room with a clock. To understand how the clock works, we begin to slowly remove the gears from them and see what happens.
Sometimes the result may be uninformative. For example, you can remove the clock hand, and then they will become a meaningless device, but their mechanism will work exactly the same. Nevertheless, with the help of this approach, it is possible to find out certain cause-and-effect and functional relationships. To determine the functions of all 25 thousand genes in humans, we will not create living people with mutations in each of the genes. But you can mess up or, conversely, turn on each of the 25 thousand genes in cells of human origin to the fullest with the help of directed genomic editing and see what happens. Now many people are doing this. It turns out that when some genes are turned off, cells simply die – this means that this gene is important for life. In the case of other genes, cells continue to live as if nothing had happened, which means that the genes corrupted in them are not important for life, at least in the conditions of cell culture. In some interesting cases, mutant cells acquire characteristic changes relative to the original cell. If you study what these changes are, you can understand why a particular gene is needed. For example, switching off certain genes can cause a cell to behave like a cancer cell. So, we can conclude that the gene we damaged is normally a suppressor of tumor development.
This kind of research is extremely useful. They do not necessarily influence medicine in terms of the development of new treatments, but they can help, for example, in the development of new diagnostic methods. Although we still do not know the genetic basis of many malignant tumors, damage to the hypothetical tumor suppressor gene mentioned above can be used for diagnosis. In the same way, it is possible to determine changes in which genes affect resistance to drugs used in cancer therapy. This information will help in choosing the optimal therapy for a particular patient.
How is gene editing better than gene modification?
Whether we like it or not, but breeds of domestic animals and varieties of agricultural plants are always derived by genetic modification. The only question is how this modification is made. Until recently, organisms with interesting properties were selected as a result of selection. The breeder allowed only some individuals to reproduce, which differed from the rest, for example, in appearance. But the reasons for these differences were genetic. As a result of artificial selection, which was carried out for many generations, there were forms whose genome was different from what it was at the beginning. In this sense, none of the agricultural products we consume is natural: it was not created by nature, but was obtained as a result of evolution aimed at improving one or another consumer property.
Gene modifications work on the same principle, only they do not involve slow selection for many generations with the culling of animals or plants that do not suit the breeder, but the removal or insertion of rather large segments of DNA, for example, the introduction of some new gene, often in a random place of the genome. Gene editing allows you to change single “letters” of DNA – its nitrogenous bases in a targeted and very precise way. This significantly expands the possibilities for creating new animal breeds and plant varieties, expands the ability to modify and improve already known GMO lines.
For example, if you have a strain that produces insulin, then with the help of genomic editing you can increase the yield of insulin, which will ultimately reduce its price. This is done most often with the help of CRISPR-Cas technology – it allows you to make an “edit" to any place of interest in the genome.
Perhaps genomic editing will solve some problems with GMOs, because GMOs will be replaced by genetically edited organisms. They may be psychologically more acceptable to many people. People usually don't like it when scientists introduce a whole bacterium gene into a plant – they perceive it as a cholera vibrio under the guise of cabbage or as a hybrid of banana and zebra. Gene editing allows you to purposefully introduce such mutations that occur naturally into the right place.
Now it is easy to determine the genome of one or another variety, understand how they differ, and then try to create an organism with a new version of the genome, partially combining the genetic changes present in the two parental forms. Let's say the English breed of Angus cows gives delicious steaks. We would like to have such a miracle at home, but we are not in England and Angus are not very comfortable with us. We would like to take some kind of Russian burenka, leave it the same unsightly, but adapted to local conditions, but make its meat similar to angus meat in taste.
To solve such a problem, we can determine the genome of an animal from both breeds, find differences between them, and try using bioinformatics methods to predict what makes angus meat the way it is, and then purposefully make these changes to the right places in the DNA of our burenka using gene editing. This task could be accomplished by long-term crosses and selection. Instead, we can work with the genome like engineers with a drawing, change something in a targeted way, evaluate the results, then take the next steps, etc. If we moved with the help of crosses, we would eventually get exactly the same result, just the process would take much longer. But since the final two objects obtained by crossing or editing the genome are genetically indistinguishable, people who are afraid of GMOs have no reason to say that the resulting animal or plant is something different.
In fact, there are "indulgences" for genomic editing even in the "draconian" law on GMOs in Russia. According to him, those organisms in which changes that could have occurred naturally are not considered GMOs. The logic is this: if we introduce the bacterium gene into plants, this could not happen naturally. But if we simply “tweak” our own genes of a plant or animal, changing some DNA letters to others, then this could happen naturally, it would just have to wait a very long time.
Is it possible to create a superman "turnkey"?
In popular culture, there are ideas that with the help of genomic editing, it is possible not only to treat simple genetic diseases by “normalizing” the DNA changes responsible for their occurrence, but also to increase IQ, improve aesthetic and physical properties of a person, etc. In the foreseeable future, this is impossible, and most likely, it is impossible in principle.
Consider this analogy: there is an Airbus A310 aircraft. It certainly fulfills its function – it flies. Most of us don't fully know how it works. If you get on a plane and you are given the opportunity to cut any of the wires and connect them to another, you are unlikely to get a new plane. No matter how you conjure with wires and tubes, you will not get an Airbus A380 from an A310, but you will certainly spoil the existing aircraft. Now let's take the situation with two planes of the same model, one flying and the other not. Having carefully studied the differences between these aircraft, you may notice that a non-flying aircraft has some specific wiring either cut or connected to the wrong place. You can make a bold conclusion from here that if you take this wire and redo the connection, like a flying airplane, then it will also fly. This is a reasonable assumption.
Genomic editing in the case of the treatment of human genetic diseases is approximately at this level. We have healthy people and people with illness. People with the disease have some common property at the level of changing the DNA sequence in a certain place, in a particular gene. Already on the basis of this, we can assume that this change is either directly responsible for the disease, i.e., is its root cause, or is somehow associated with the disease. It's good if there are still studies by geneticists that show that the disease is inherited, along with the detected change in the genes. We can think of a person with a disease in terms of a non-flying airplane with incorrectly connected wiring. We can change this wiring, or, in this case, the DNA letter, to the one that is present in healthy people. Genomic editing allows you to do this, but most often only at the embryo stage, and such manipulations are prohibited by law. But it is possible in principle. Here we are not improving anything – we are rather bringing it back to normal.
Improving healthy people, so as not to be covered by this term, is a completely different task, akin to the production of one aircraft from another through minor alterations and rearrangements. It is easy to spoil a complex system, but it is difficult to improve in a given direction, since positive changes cannot be guaranteed due to its emergence, the interconnectedness of parts. I'm not saying that for this it is necessary to be sure that some people are genetically better than others – and this is far from a fact.
A simple example of how complicated the connection between genes and properties that we see with the naked eye is a recent article [3] in the journal "Science". As you know, human growth is largely genetically determined. Scientists have found about 10 thousand genetic markers associated with growth, despite the fact that a person has only 25 thousand genes. This means that a significant proportion of our genes contribute to our growth – but the role of each of them is minimal. That is, even such a “simple” parameter as height turned out to be such a multifactorial thing that the result actually makes any work on creating a “turnkey” person with a given height meaningless.
Coupled with cloning, the issues of genetic modification and editing of people are closely related to bioethics and fears living in society. In the context of these fears, initiatives are also emerging to limit research related to genome editing. For example, there are rumors and urban legends that scientists in the laboratory can potentially start creating universal super-soldiers. Fortunately or unfortunately, this occupation is unpromising when it comes to people.
Let's say we decided to create soldiers and took, for example, Nikolai Valuev as a “model” – rightly deciding that his good physical data would be optimal for creating clone soldiers. With the help of editing, we will tweak some genes in the cells taken from the original, hoping to increase physical endurance or the ability to obey orders without question (although we do not know which genes are responsible for this and whether they exist at all), and then we will clone, just as Dolly the sheep was done 25 years ago and we will plant eggs with Valuev's improved DNA to hundreds of surrogate mothers. When we have a hundred newborn designer babies, they will be like identical twins in relation to each other, i.e. they will be almost identical to each other in terms of genetics. But then they will all have to be brought up, and at the stage of education, differences will inevitably arise, which will only grow during those 15-18 years until future soldiers reach “marketability". We will get completely different people with different abilities and inclinations. In addition, so much will happen during this time that the whole enterprise will become meaningless, these clones may simply not be needed, doctors or teachers will be needed, for example. In general, it is much easier to indoctrinate and train existing people – this is evidenced by the sad experience of Hitler's Germany and the Stalinist Soviet Union. Indoctrination of people is not at all hindered by the fact that they are genetically different.
Will gene therapy help against aging?
Many have high hopes for the use of gene editing to combat aging, especially after recent high-profile press releases: “CRISPR/Cas9 therapy suppresses [4] aging, improves health and prolongs life in an experiment on mice.” I am skeptical about this. At least because this effect is actually shown [5] only for mice with progeria, a disease that accelerates aging due to a breakdown in a single gene. It is technically quite feasible to fix this at the present stage, but it is at the level of restoring the correct wiring in a damaged aircraft.
There are more common conditions, for example, age-related macular degeneration, in which retinal cells gradually die and vision deteriorates. This condition has a high heredity, and its ”culprit” genes are known [6]. CRISPR/Cas9 therapy for retinal diseases is currently being actively developed [7] and it is hoped that some patients with age-related macular degeneration will regain their eyesight due to local gene changes in the corresponding cells of the elderly.
But natural aging is a much more complex process than progeria and even age–related macular degeneration. It occurs in all tissues, not only at the DNA level, and damage can be different in different cells. One of the causes of aging is reactive oxygen species, which are formed in our mitochondria simply because we live, move and eat. They damage cells and lead to the fact that our body is slowly “falling apart". Even if most aspects of aging are determined by the state of DNA, we currently know too little about the function of our genes – about 90% of them have not been studied and to identify the genes responsible for aging, if any, is a separate big task.
Why will gene editing be necessary in the future?
Genetic engineering will continue to develop in the field of agriculture, and this development will largely occur due to the creation of genetically edited organisms. With regard to embryonic editing of people, the development of technology will be delayed, since the accuracy of the technology will need to be brought to some level in order to exclude or reduce to an acceptable minimum the frequency of undesirable DNA changes that will affect the health of the future, unborn person. It will be difficult to achieve this.
If the ban on embryonic editing will exist for a long time, then the treatment of human diseases with this technology will be carried out at the organ level. For example, in a person suffering from cystic fibrosis, all cells are genetically defective. But the lungs suffer the most. So, in order for people with such a disease not to die at the age of 30, it is necessary to find a way to effectively deliver genetic editors into lung cells in order to “return them to normal”. It is unlikely that a general solution will be found, but, of course, it is necessary to learn how to deliver targeted genetic editors to most cells of the liver, lungs, pancreas, and so on – complex organs consisting of tens of billions of cells. In essence, this is the same task that limits targeted cancer therapy. We have monoclonal antibodies to target tumor cells, but we can't get them exactly where they need to be.
But it will probably be necessary to develop more “radical” technologies of embryonic editing in the end. If we look decades ahead, then, unfortunately, we can expect that the frequency of “bad” gene variants transmitted to descendants will grow. This happens because with the development of healthcare, we are partially getting out of the action of natural selection. If back in the XIX century, eight out of ten children died in infancy, which could be considered as selection, now, thank God, this does not happen.
However, if we recognize that in this way those people survive and reproduce who could not do it under conditions of stricter selection, then the burden of mutations in all of humanity increases. At the same time, a “bad” combination of genes from the point of view of viability does not mean a hopeless person from the point of view of the whole society, it is enough to recall Stephen Hawking. But sooner or later it may happen that the accumulated genetic load will reach a certain limit and fertility and viability may begin to fall rapidly, despite the further development of medicine. And then one can imagine that genomic editing will be widely used at the stage of conception or at the level of the germ cells of the parents. As in the case of gene therapy, variants of genes that have been proven to impair viability will change. These will be the same “turnkey people”, but not made to be “faster, higher, stronger” than ordinary ones, but simply able to live, despite the presence of a huge number of changes in DNA that determine their genetic individuality.
Literature
- Rituximab. Wikipedia
- Bevacizumab. Wikipedia
- Jocelyn Kaiser. «Landmark» study resolves a major mystery of how genes govern human height. 2020
- Salk Institute. «CRISPR/Cas9 therapy can suppress aging, enhance health and extend life span in mice». 2019
- Ergin Beyret et al. Single-Dose CRISPR/Cas9 Therapy Extends Lifespan of Mice with Hutchinson-Gilford Progeria Syndrome. 2019
- Maller, J., George, S., Purcell, S. et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. 2006
- Peng YQ, Tang LS, Yoshida S, Zhou YD. Applications of CRISPR/Cas9 in retinal degenerative diseases. 2017
About the author: Konstantin Severinov – Doctor of Biological Sciences, Professor of the Skolkovo Institute of Science and Technology (SkolTech), Professor at Rutgers University (USA), Head of the Laboratory of Molecular, Environmental and Applied Microbiology of Peter the Great SPbPU.
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