Gene drive in mammals: details

How to control evolution and turn everyone into albinos

Alexey Aleksenko, "Snob"

Engels also suggested gradually moving from knowing the world to changing it, but in some areas of knowledge it turns out better, and in some worse. For example, to increase the number of satellites of the planet from one to fifteen thousand – no problem. We also did not hesitate to increase the electromagnetic radiation of the Earth in the radio range tens of thousands of times in just a hundred years. But for some reason it is customary to approach biology with restraint. Maybe it's because we are biology ourselves.

There is another reason: biology itself somehow began to change even before it, according to Engels, had time to really know it. So many people have bred that many species of living creatures are rapidly disappearing. But others are doing well: for cockroaches, mice, influenza viruses and HIV, this world has become much more hospitable. Invasive species that spread across the planet not without human involvement, in some places specifically live with the light of peaceful and defenseless native animals like marsupials of Australia. And here it would be just nice to intervene, to adjust something. There is, of course, the risk of making a mistake and making it even worse, but, returning to Engels, let's remember that the bearded classic still offers to find out everything exactly first, and only then to sculpt in his own way. This principle, if carried out consistently, guarantees against unpleasant surprises.

One of the directions proposed by scientists for reshaping the entire biosphere to their taste is gene drive. This is exactly what geneticists from the University of California at San Diego have learned to do, and they have achieved success not with some boogers, but for once with mammals. From them, as we understand it, to humans is not even one step, but zero, because humans are mammals themselves. Let's tell this story in a little more detail.

Genetics: a brief briefing

We tried to tell you about what a gene drive is a couple of years ago, so let's briefly recall. During sexual reproduction, dad's and mom's chromosomes are connected in one cell, and then they exchange sections among themselves in order to properly shuffle the genes. As a result, the genes are distributed among the descendants approximately equally, so that neither mom nor dad would be offended. However, there is one loophole in the very mechanism of gene shuffling that allows you to cheat. The fact is that this shuffling begins with a break in one of the chromosomes (for example, dad's). After that, the gap widens a little, so some dad's information may be lost. And at the very end, this hole is sealed according to the pattern of another chromosome (mom's). Thus, if all this happens, for example, in the gene encoding dad's charmingly expressive look with a haze, then it may well happen that none of the kids will inherit it: looking into their meaningless piggy button eyes, all grandmothers will enthusiastically shout that the kids were born into mom.

Now imagine an evil, selfish gene who decides to use this trick to gain an unfair advantage. If he learns to find a similar place on the partner chromosome and make a gap there to start the exchange, then he will be able to be transmitted not to half of the descendants, but to a slightly larger proportion, and ideally to everyone at all. Such genes do exist, and the whole described mechanism is called "gene drive".

Geneticists using the CRISPR-cas9 gene editing technique have learned to use this trick to prevent malaria mosquitoes from spreading the infection on earth. Everything worked out with mosquitoes, but somehow the mammals were in no hurry to submit to the will of geneticists. Until recently. And then the geneticists overreached them, and that's how.

How was it all

To make the results of the experiments clearer, they decided to manipulate the tyrosinase gene. This gene encodes an enzyme that converts the amino acid tyrosine into a dark pigment that gives mice a mouse color. If the gene is destroyed, the mice will be white. If you cross white mice with ordinary mice, everything will happen according to Mendel's laws: chromosomes with an active and killed gene will be scattered equally among the descendants. But if you give the "white" gene the ability to drive, it will become more and more from generation to generation. This is no longer a "Mendelian" inheritance, but a "Supermendelian" inheritance, which is reflected in the title of the scientific article.

The driving force behind the study were two ladies: student Hannah Grunwald and Professor Kimberly Cooper.

Besides Kimberly, the project was also led by Valentino Ganz, the same one who three and a half years ago made a gene drive system for malaria mosquitoes. In two years of laboratory tinkering, they managed to make a gene that can spread in mice much faster than the laws of classical genetics allow. He was called CopyCat (translated as "copycat" – for example, a criminal who deliberately reproduces the creative handwriting of a homicidal maniac). The CopyCat element really turned out to be merciless, but it does not copy someone so much as it makes you copy yourself, as someone who intends to selfishly use the gene drive for their own reproduction should do.

If one of the readers is interested in exactly how CopyCat works and how the whole mechanics of CRISPR-Cas9 is built into the tyrosinase gene, you can look at the picture from the press release of UC San Diego Researchers First to Use CRISPR/Cas9 to Control Genetic Inheritance in Mice.

Let's tell everyone else that the gene drive was a success. In some mouse families, 86% of the mice inherited the CopyCat element instead of the usual gray mouse skin gene. And they were ready to pass this aggressive thing on to their children.

However, not all of them. Unexpectedly for the researchers, it turned out that CopyCat is able to "drive" itself only on the maternal side. When transmitted from the mouse dad, it is inherited as a normal corrupted tyrosinase gene, that is, strictly as bequeathed by Gregor Mendel. The authors discuss in the article Super-Mendelian inheritance mediated by CRISPR–Cas9 in the female mouse germline, what is wrong with males compared to females. We will not interfere in their conversation, but we will remind readers about how differently mom's and dad's genes are inherited, and not in mice, but in real people-Icelanders. There is definitely something important and biological here, but since this important thing has not yet been discovered, we will end the narrative at this point. Let the reader appreciate the fact that even with our poor coverage of biological problems, two notes from different sides touched on the Unknown at once. It's from such things that some people itch to do science; and others don't give in to anything.

Views for the future

So, we have a technology that allows us to control the evolution of mice. The researchers say that the purpose of the work was to create a tool for laboratory research (for example, drawing clean lines), but there is no talk of "driving" mice in nature yet. But our idle fantasy knows no barriers. It is possible, for example, to distribute among all the mice of the Earth genes that prevent them from carrying rabies. Or, say, to make all rodents infertile, who have voluntarily settled some beautiful island and threaten the local exotic fauna.

To engage in genetic engineering of mice on a distant island is a tempting idea: unlike winged mosquitoes, mice have practically nowhere to go from the island, and whatever scientists have injected them with, they will not carry it further. On the other hand, genetically, a mouse is very, very similar to a human - much more similar than, for example, the same mosquito. In particular, on the long arm of the 11th chromosome, we have the TYR gene, which is indistinguishable from the mouse, with which researchers from California worked. In the event of a CopyCat leak from mice to humans, after a couple of thousand generations, the planet will be inhabited by albino people. Looking into the beautiful brown eyes of the characters on the Renaissance canvases, these descendants of ours will remember the inventors of CopyCat in such words that they will turn over in their coffin many times.

However, this plot is absolutely fantastic. People with mice do not seem to have exchanged genes yet, and it is unclear why this could happen. Recall that the UN Convention on Biodiversity rejected the idea of banning gene drive as a potentially dangerous technology, because it considered that laboratory research definitely does not threaten anything, and when it comes time to release something capable of driving into nature, scientists will be careful enough not to stick nonsense. But the fact that we now know how to control the evolution of mammals still inspires some hope.

Here is one example. Chinese doctor He Jiankui has learned how to edit human genes so that a person is immune to HIV. "Why?! critics shouted. – In this way, it will still not be possible to make all mankind sustainable, because it is impossible to force all people to reproduce with the help of IVF. And to expect that the gene will spread through selection is like wishing humanity to fall victim to the HIV pandemic." Well, now there is an answer to the skeptics: the resistance gene, like any other desired improvement of human nature, can be distributed with the help of a gene drive. There is something to think about until some ethics committee knocks these thoughts out of our heads with a series of ringing slaps on the back of the head, as, in fact, happened with He Jiankui.

It is not a fact that the gene drive will be useful for people to somehow change the biosphere of the earth or even themselves. The fact is that now they can do it. And what all this will lead to – well, you just have to wait and see for yourself how everything will be in the future. It remains to wish readers who will live to see only good things there.

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