15 March 2022

From a cannon by genes

What's wrong with "ethnically oriented" weapons

Polina Loseva, N+1

The Russian Ministry of Defense claims that Ukrainian laboratories could be engaged in "the creation of bioagents capable of selectively infecting various ethnic groups, in particular Slavs." Apparently, this means a genetic weapon — one that will accurately distinguish a Slav from a non-Slav and will not harm "their own". Genetic technologies do not stand still, but no one has seen such weapons yet. We regularly write about modern biotechnologies and everything we know about them confirms that the creation of a "genetic cannon" is, firstly, a senseless enterprise, and secondly, impossible.

"Conventional" biological weapons should act on all people in approximately the same way. Bacteria or viruses are illegible and infect everyone without paying attention to the cut of the eyes or pigmentation of the skin. In order for a weapon to hit representatives of one ethnic group and spare all the others (which not even every anthropologist can easily distinguish, not to mention ordinary people), its guidance must work at the level of genes.

But we still have to get to the genes. First, the "ethnic weapon" needs to get inside the body, then inside the cells of this body, find the genome there, search for the target sequence of nucleotides on it, and if it is found, "shoot" — that is, somehow harm a person.

In recent years, scientists have really developed technologies that allow selectively recognizing and targeting specific areas of the human genome — to treat people from sickle cell anemia, blindness, amyloidosis or HIV (this is called gene therapy). And since the spring of 2020, we have been closely following how biologists have hastily created a system for delivering coronavirus genes into the cells of billions of people — that is, vaccines. It wasn't easy for all of them. And many problems — common to geneticists, doctors and hypothetical developers of "ethnic weapons" — as practice shows, have not yet been solved.

How to get inside the body?

All the gene therapy drugs that we have ever written about are injected into the body: sometimes directly into the problem organ, for example, into the eye, sometimes intravenously. No one has come up with other delivery options yet, because such molecular structures are quite large. These are at least two strands of RNA or RNA and protein (if we are talking about the popular CRISPR/Cas system) — and they can't get into the body through the mucous barrier in the intestine or nose.

Even most coronavirus vaccines — both vector and mRNA — are administered only intramuscularly, although they need to deliver only one fragment of DNA and RNA to the cell. Some companies, however, develop nasal forms of drugs, in the form of a spray. But the vaccine delivered in this way will not enter the bloodstream. It will work only at the level of the nasal mucosa, and all its effects will already be a consequence of the work of local immunity (this is our text "We will introduce orally"). Therefore, nasal genetic weapons can only hit a part of the cells in the victims' nose. To seriously harm a person, you need to deliver him immediately into the blood.

American scientists from the Center for Nonproliferation Studies (James Martin Center for Nonproliferation Studies) in their 2021 report on the prospects of biological weapons suggested that insects, like the same mosquitoes, could become such a delivery system, which successfully cope with the transfer of various infections. But in this case, you will have to figure out how to make the molecular structure survive in the mosquito's body: it does not fall apart and is not washed out of the salivary glands.

In general, there are problems with the delivery of genetic weapons. In whatever form it is released, the probability that it will enter the victim's body is quite small. Perhaps mass "vaccination" of the population would help here — but, as practice has already shown, it can be handled in Russia is problematic even for the Russian authorities. What can we say about a likely opponent.

How to get inside the cage?

Not everything that floats in the blood automatically gets inside the cells. Therefore, the developers of gene therapy have been struggling for a long time over how to teach cells to "swallow" medicine. So far, they are doing the opposite: they force the drug to invade the cell. They are dressed in a shell from a real virus, which helps the drug infect the cell.

The same way, for example, adenovirus vaccines like Sputnik V are arranged. In mRNA vaccines and some types of gene therapy, a lipid envelope is used.

But the shell increases the size of the active particle. Now it is even more difficult for her to pass through the mucous membranes, and indeed through any barriers in the body — and these separate the blood from many organs, for example, from the sensory organs, lungs or sex glands. Therefore, the drug will be relatively easy to penetrate only into organs that are well supplied with blood (perhaps that is why many pilot projects in the field of gene therapy target red bone marrow or liver). And the neurons of the brain, for example, cannot be reached in this way at all.

So the creators of a potential weapon will have to come up with a specific organ that will become a target, and even such that it is easy to get into it. Otherwise, the weapon will "spread" through the body — and lose effectiveness.

How to recognize an ethnic group?

Let's assume that a hypothetical weapon still broke into some cells and got into their nuclei. Then, unlike the medicine for which doctors think, he needs to "decide" whether to act or not. And to do this, you need to identify your target — some part of the genome that is found only in those targeted by the creators of weapons.

Since the early 2000s, articles have been published every now and then predicting that such sites - by which one group of people can be clearly distinguished from another — will be discovered, and genetic weapons will become possible. It started after the human genome was finally read in 2001 (we wrote about this project in the text "Human Genome: Twenty years later"). Moreover, projects have been launched to study the diversity of these genomes: scientists have undertaken to sequence the DNA of thousands of individuals to find out in which positions their genomes differ and whether they can somehow be classified.

These projects resulted in a rethinking of what race is. If earlier anthropologists focused on the external signs of people to describe them, now they began to operate with single-nucleotide polymorphisms (that is, point substitutions) and other minor differences in the genome. And it turned out that from a genetic point of view, race is not a set of genes that people of other races do not have. This is a set of point variations in the genetic text that occur with a certain frequency. That is, relatively speaking, an increased probability of finding options A, B and C and reduced — for D, E and F.

Therefore, it is difficult to determine which race a person belongs to by simply reading his genome. To do this, you need to check which nucleotides are located at several hundred points in its genome. And even after that, there is a chance that he will turn out to be something in between the two races - for example, due to the fact that his ancestors repeatedly moved from place to place and married with the locals. And the differences between individual nationalities, especially neighboring ones, will be even more difficult to detect in this way.

In any case, in order to point a weapon at people of a particular race (not to mention an ethnic group), it is necessary to incite the genetic recognition system to several tens, if not hundreds of points at once. This means delivering hundreds of RNA molecules to the cell at the same time (so many will not fit into either a lipid particle or a viral vector). And even if it succeeds, they will almost certainly not be able to work in all places at the same time.

This means that extra victims are inevitable — false positive "shots". Misfires are also inevitable — in most cases, the weapon will target only a part of the regions in the genome, and the effect will be weaker than the one the creators hoped for.

How to harm?

There are also problems with what can be a "shot" — it is not very clear what effect can be achieved with such a weapon after it has recognized its target.

Modern DNA recognition systems cannot "turn on" a virus or incite a bacterium on a cell. They only know how to make a point change to the very place in the genome that they have learned. Here, for example, is what the CRISPR/Cas "molecular scissors" are capable of, depending on which Cas protein the system uses: change one nucleotide to another, or hang an epigenetic label (that is, turn on or off the gene), or cut DNA in one place, or cut a large one out of it plot.

Another option is to make changes to the work of the cell at the RNA level. That is, the genes themselves remain intact, but their products do not work (this can also be achieved using the same CRISPR/Cas system or RNA interference), and the corresponding protein does not appear in the cell.

Here, perhaps, the creators of weapons will have an easier time than the developers of drugs. Breaking is always easier than building. Actually, that's exactly why they are currently testing mainly such methods of gene therapy that disable an incorrectly functioning gene.

But it should be borne in mind that cells, as a rule, resist. DNA repair systems search for and patch up breaks, a second copy of the gene comes into play instead of the first, and if the damage is too serious, the cell triggers apoptosis. The efficiency of CRISPR/Cas never reaches 100 percent. This means that the effectiveness of genetic weapons in cells will be low. And the maximum that it will be able to do is to make many small cuts in the DNA and push the cell to suicide. And this does not necessarily affect the life of the whole organism — especially if the concentration of weapons in the blood is low and it is dispersed to different organs and tissues .

Are there any other ideas?

Does this mean that "ethnic" weapons are impossible? Perhaps, yes. There are too many barriers separating us at the current stage of the development of science even from genetic weapons of mass destruction — that is, one that would attack the genome of people, regardless of race, ethnicity and sexual orientation. But even if such a thing could be invented, it is impossible to imagine a system that would recognize and cut hundreds of targets in the genome at the same time point-by-point and without misfires.

One can only fantasize about what a bypass road might look like — a situation in which a victim population is created artificially. American scientists in their report tried to imagine such a two-stage construction: first, genetic weapons are indiscriminately directed at a certain group of people (that is, they choose victims based on territorial characteristics, not ethnic ones), which makes a single edit to their genome — for example, turns off some gene in their cells that is important for resistance to one or another infection. And at the second stage, people are already affected by "ordinary" biological weapons, for example, they are infected with a virus or a bacterium.

This way, of course, allows you to bypass the problem of racial identification at the genome level. But it creates new problems: you need to find a disease that normally passes easily, but becomes dangerous or fatal in the absence of a specific gene. We don't seem to have any good examples of such a disease. You can only turn off one of the genes responsible for the work of the immune system and thereby cause immunodeficiency. But to do this, you need to get into the vast majority of cells in which this gene works. And even if it is possible to solve problems with delivery to the body, distribution throughout the body, recognition and editing of genes, then it will be necessary not to miss the spread of the second component of the plan, a bacterium or a virus — which makes the probability of success even less.

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