3 billion years ago, bacteria developed a very effective defense against viruses: every time one enters their body, they store part of their genetic material in a kind of 'library', from which they extract the appropriate 'tome' each time. time a similar virus tries to infect them. With this information, they search your DNA strands, cutting out the embedded harmful sequence and stopping the condition in the bud. A relatively simple method that, however, science also became aware of relatively recently. It was the Spaniard Francis Mojica who in the summer of 2003 realized that it was a kind of 'natural autovaccine' for bacteriophages. He named it 'Clustered Regularly Interspaced Short Palindromic Repeats', or CRISPR. Years later, in 2012, researchers Emmanuelle Charpentier and Jennifer Doudna published in 'Science' how to transfer this mechanism to other living beings - which is why they won the Nobel Prize in Chemistry in 2020. This was the first chapter of an entire scientific revolution that we can already see today. And even eat.
Known as the 'genetic cutter and glue', CRISPR technology is a kind of 'scissors' composed of some guides and a protein (the best known is Cas9, but others are already used, such as Cas12 or Cas10) that can be programmed to search for, join and cut a specific DNA sequence. Something that allows you to edit almost any cell and create in the laboratory from malaria-carrying mosquitoes without the 'genetic impulses' that force them to bite people, through the modeling of diseases in the laboratory to study them like never before or the (still ) promise of therapies that eliminate disease-causing genes.
What is the genetic 'glue cutter'?
How does CRISPR work?
This technology uses guides and a protein (Cas9, although others such as Cas 10 or Cas 12, with different properties, are also used) to target selected areas of the DNA and cut. From there, the cut ends can be glued together and the gene inactivated, or DNA templates introduced, allowing its “letters” to be edited at will.
What are its applications?
It can be used in almost any situation where you want to modify a DNA sequence. That is why it is being very useful in basic research to generate models of diseases that could barely be studied before, as well as to study new targets and drugs. It also allows the production of new plants in which no gene is introduced - as occurs in transgenics - but rather an existing one is modified.
What are its limitations?
The technology still needs to be refined: sometimes larger fragments than desired are cut, or the DNA is rearranged in unforeseen ways, giving rise to unexpected alterations. This is the main obstacle in its application in humans.
Are there ethical implications?
Yes. Since its origin, CRISPR has raised a series of ethical questions, even more so since the case of the Chinese scientist who modified human embryos from which three girls were born. The technique opens the possibility of creating 'humans on demand', increasing capacities such as learning or memory. This is why many researchers are calling for an in-depth discussion by the entire scientific community.
"A few years ago I would have said that all this was totally impossible," states Lluis Montoliu, researcher at the National Center for Biotechnology of the CSIC (CNB-CSIC) and one of the greatest technology experts in Spain. He explains that his team came across CRISPR "by serendipity", a fortunate discovery due to being in the right place at the right time: an Italian student who was part of his team traveled to Switzerland for a temporary stay just at the time he was there. new tool landed. «He learned everything he could and then came back. "It changed our lives." Thus they were able to launch experiments that they had been working on for two decades with other, much more complex and expensive methods. «It worked so well that at first we didn't believe it. Because for less than 100 euros you can start working. The limit is in the imagination of those who use this tool," he says.
The team uses CRISPR to investigate albinism, a disease that we know because of the lack of pigmentation of those who suffer from it, but which manifests other more serious problems such as low visual acuity (the European Union considers them legally blind). Montoliu performs genetic tests on Spanish patients and their families to determine which specific gene is affected (since there are up to 22 types), and then creates what he has dubbed the 'avatar mouse', accurately reproducing the disease, allowing it to be studied in depth. "The limit of this technology is the imagination of those who apply it," he says.
In fact, the first clinical trials already exist to test the effectiveness of immunotherapy treatments against cancer, two common blood diseases (sickle cell anemia and beta-thalassemia), and for the fatal condition of transthyretin amyloidosis. But there are dozens of experiments waiting to get the green light for human testing. «It has no limit. There are millions of bacteria, and each one has a different CRISPR system. And you don't have to go far to find them: in the pot on your balcony you have thousands of candidates to produce a new tool, who knows with what particularity.
Biohackers and dangers
The year was 2013 and molecular biologist Miguel Ángel Moreno Mateos moved to Yale University to carry out his second postdoc. "Come on, look at this CRISPR thing and see if it looks good," his boss, the renowned researcher Antonio Giráldez, told him. "I didn't even know what it was," Moreno Mateos confesses to ABC, "nor did I imagine the revolution of this tool." His team at the Andalusian Center for Developmental Biology investigates the first steps in embryonic development using zebrafish as a model. "The beginning depends on the egg, on the maternal contribution, which is responsible for activating the zygotic genome that is silent at the beginning." With CRISPR technology they activate and deactivate genes to understand what precisely the origin is, that 'click' that triggers a new living being.
A living being that in the future will be possible to generate artificially thanks to this genetic technology. In fact, just this week, Chinese scientists claimed to have been able to create a baby mouse from the egg of a female who did not have sex or receive sperm from a male, editing her egg with this novel technique. It is the first case of artificial parthogenesis in mammals, something that until recently was believed to be impossible.
"We are turning science fiction into real science," says Moreno Mateos, who also highlights the democratization that the system has brought about, both for its simplicity and its low cost: with just 100 euros it is possible to buy a CRISPR kit. However, he emphasizes that although it is a true revolution, it is not going to be the panacea to all our problems: "It is going to be very difficult to have a little pill that will fix us," he points out. And, furthermore, it carries its risks. The clearest example was the case involving Chinese researcher He Jiankui, who crossed all limits and modified several human embryos with CRISPR from which three girls were born. Today, he is in prison and little is known about those minors, 'designed' to be resistant to the HIV virus (an objective that, according to the little existing information, was not achieved).
At that time, the entire scientific community united to condemn the experiment for its complete lack of ethics. The only voice that dissented was that of geneticist George Church, who claimed his "right to a balanced opinion." "Let's be quantitative before accusing (...) We have pigs that have dozens of CRISPR mutations and a mouse strain that has 40 CRISPR sites that are constantly activated, but we have no evidence of negative consequences," defended the researcher in an interview for 'Science. '. He himself is the architect of the controversial project to 'resurrect' mammoths by inserting their genes into the DNA of a living elephant. But not with the final intention of reviving this extinct animal, but to avoid climate change: their idea is to transfer these woolly elephants (as they would not actually be mammoths, but rather a current elephant hybrid with characteristics of this extinct animal) to Siberia so that they cut down trees, trample the land and thus build an entire 'vegetable carpet' that protects the permafrost and stops the thaw.
«It is a revolution, it is true. And this technology has enormous potential. But we also have the responsibility to educate society and teach it that being a 'biohacker' leads nowhere," says Moreno Mateos.
CRISPR 'Flavor'
But if there are some areas in which Crispr applications are already a palpable (or, rather, edible) reality, they are livestock and agriculture. Among them, lambs and cows modified to produce better meat, mushrooms that last longer without turning black, apples that do not rot when they fall to the ground, tomatoes that help control hypertension or fish without bones, as a group of researchers has just achieved. in China. They have achieved this with crucian carp, a fish very popular for its tender meat, but its small intramuscular spines can get stuck in the throat and make its industrial processing difficult.
In Spain, a team led by Francisco Barro Losada, from the CSIC Institute of Sustainable Agriculture, is working on wheat suitable for celiacs. «We inactivate the gene that generates gluten; Thus it is not expressed in the plant and the wheat it produces is suitable for celiacs," Barro Losada explains to ABC. He clarifies that, in reality, this wheat is not genetically manipulated, but rather a redesign of the plant is carried out that later creates the grain. «It is the same process that humanity has been doing for the last 10,000 years; “CRISPR is just a finer control of all that development.” The researcher insists that it is a tool, not an end. "It's like in medicine: before we operated with a saw, now with a scalpel."
Although not all governments seem to agree on this point. While in Japan or the US they almost legislate at the same time that new advances emerge, regulating these crops and their commercialization, the European Union is suspicious: these types of foods in which CRISPR is used are considered within the group of genetically modified ones (in the same bag as the controversial transgenics, although in the case of the 'genetic glue cutter' genes are not implanted, but only cut) and their cultivation is prohibited. Although its importation from other countries is not the case. «We can buy them, but not plant them here and control production. "We are losing a huge opportunity," says Barro Losada, who for this reason has to carry out his tests in plantations in South America. «It makes no sense because it is going to be the tool of the future: it will allow us to create crops that are more resistant to heat or that need less water, vital in a context of climate change. "People have to lose their fear of technology, it is made to help."
Patent war
With all this at stake, it is not surprising that a war has begun to control a patent that can bring enormous economic benefits. After a long legal battle, the US Patent and Trademark Office (USPTO) a few weeks ago attributed the invention to Feng Zhang, a neuroscientist at MIT's Brad Institute - who applies CRISPR in psychiatric diseases -, leaving out his creators, Charpentier and Doudna, who have lost the intellectual property rights for the commercialization of this technology and the power to decide who will use it, at least in the US. Legal disputes aside, the revolution seems unstoppable: CRISPR is here to stay .