Fish without bones, fruit that does not rot, or gluten-free wheat, gene editing is a reality in livestock and agriculture
Its use to alleviate human diseases is still very incipient
3,000 million years ago, bacteria developed a very effective defense against viruses: every time a virus enters their body, they store part of their genetic material in a kind of ‘library’, from which they take 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 its tracks. A relatively simple method that, however, science also realized relatively recently. It was the Spaniard Francis Mojicawho in the summer of 2003 realized that it was a kind of ‘natural self-vaccine’ of bacteriophages. He named it ‘Clustered Regularly Interspaced Short Palindromic Repeats’, or CRISPR.
Years later, in 2012, the researchers Emmanuelle Charpentier and Jennifer Doudna published in ‘ Science ‘ the way 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 cut-paste, CRISPR technology is a kind of ‘scissor’ made up of 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 sequence of DNA. Something that allows almost any cell to be edited and created in the laboratory from malaria-carrying mosquitoes without the ‘genetic impulses’ that force them to bite people, passing through the modeling of diseases in the laboratory to study them like never before or the (yet ) promise of therapies that eliminate disease-causing genes.
What is the genetic ‘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 already 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 inserted, allowing its “letters” to be edited at will.
What are your applications?
It can be used in almost any situation where it is desired to modify a DNA sequence. For this reason, it is being very useful in basic research to generate disease models that could hardly 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 is the case with transgenics-, but rather an existing one is modified.
What are your limitations?
The technology still needs to be fine-tuned: sometimes larger fragments than desired are cut, or DNA rearranges itself in unexpected ways, leading to unexpected alterations. This is the main obstacle in its application in humans.
Are there ethical implications?
Yes. Since its inception, CRISPR has raised a number 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 à la carte’, increasing capacities such as learning or memory. That is why many researchers ask for an in-depth discussion from the entire scientific community.
“A few years ago I would have said that all this was totally impossible,” says Lluis Montoliu, a researcher at the CSIC’s National Center for Biotechnology (CNB-CSIC) and one of the leading technology experts in Spain. He explains that his team came across CRISPR “by serendipity”, a lucky find because it was 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 when this new tool landed. “He learned all he could and then he came back. He changed our lives». In this way, they were able to give an outlet to experiments in which they had been working without much success for two decades with other methods, much more complex and expensive. “It worked so well that at first, we didn’t believe it,” he says.
The team uses CRISPR to investigate albinism, a disease that we know due to 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, being able to study it in depth. “The limit of this technology is in the imagination of the person who applies it,” she says.
In fact, the first clinical trials are already underway to test the efficacy of immunotherapy treatments for cancer, two common blood diseases (sickle cell anemia and beta-thalassemia), and the deadly ailment transthyretin amyloidosis. And 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 very 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 the molecular biologist Miguel Ángel Moreno Mateos moved to Yale University to do his second postdoctoral degree. “Come on, look at this CRISPR thing to see if it looks good,” his boss, the renowned researcher Antonio Giráldez, told him. “He didn’t even know what it was,” Moreno Mateos confesses to ABC, “nor did he imagine the revolution of this tool.” His team from the Andalusian Center for Developmental Biology investigates the first steps in embryonic development using the zebrafish as a model. “The beginning depends on the ovule, on the maternal contribution, which is in charge of activating the zygotic genome that is silent at the beginning.” With CRISPR technology, they activate and deactivate genes to understand precisely what 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, this very week, Chinese scientists claimed to have been able to create a mouse pup 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 parturition in mammals, something that until recently was believed to be impossible.
“We are turning science fiction into real science,” says Moreno Mateos, who also underlines the democratization that the system has brought about, both because of 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 will not be the panacea for all our problems: “It will be very difficult to have a little pill that will fix us,” he points out. And, in addition, it carries its risks. The clearest example was the case involving the Chinese researcher He Jiankui, who crossed all limits and modified several human embryos with CRISPR.of which three girls were born. Today, he is in jail 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 came together to condemn the experiment for its total lack of ethics. The only voice that disagreed was that of the 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: his idea is to move these woolly elephants (because they would not be mammoths in reality, but a hybrid of a current elephant with characteristics of this extinct animal) to Siberia to cut down trees, trample the ground and thus build a whole ‘vegetable carpet’ that protects the permafrost and stops the thaw.
“It’s a revolution, it’s true. And this technology has enormous potential. But we also have a responsibility to educate society and teach it that being a ‘biohacker’ leads nowhere”, says Moreno Mateos.
CRISPR ‘flavor’
But if there are any areas where Crispr applications are already a palpable reality (or, rather, edible), those 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 boneless fish, as a group of researchers have just achieved in China. They have achieved this with crucian carp, a very popular fish for its tender meat, but its small intramuscular bones can get stuck in the throat and make it difficult for industrial processing.
In Spain, a team led by Francisco Barro Losada, from the CSIC’s Institute for Sustainable Agriculture, is working on wheat suitable for coeliacs. “We inactivate the gene that generates gluten; This is not expressed in the plant and the wheat it produces is suitable for celiacs, “explains Barro Losada to ABC. He clarifies that, in reality, this wheat is not genetically manipulated, but rather a redesign of the plant that later creates the grain is carried out. “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 you 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 as new advances appear, regulating these crops and their commercialization, the European Union is suspicious: this type of food in which CRISPR is used is considered within the group of the genetically modified (in the same bag as the controversial transgenic, although in the case of the ‘genetic glue’ genes are not implanted, but only cut) and their cultivation is prohibited. Although not so its importation from other countries. “We can buy them, but not plant them here and control the 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 doesn’t make sense because it’s 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 the 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 the Broad Institute of MIT -which applies CRISPR to 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 battles aside, the revolution seems unstoppable: CRISPR is here to stay.
