Before becoming one of the Spanish creators most relevant of the last century, the sculptor and poet Jorge Oteiza executed his first large stone mural in an unusual location: the Livestock Artificial Insemination Institutecreated by dictator Francisco Franco in 1947, on the outskirts of Madrid. Oteiza imagined copulating animals and sculpted majestic abstract figures, which today preside over an unexpected monumental entrance to a scientific livestock facility. The first genetically edited farm animals in Spain were born here in May 2017: 12 rabbits with a gene inactivated to study its role in fertility. And this is where Teodoro was born on July 14, the first Spanish lamb with DNA modified in the laboratory.
The Veterinarian Pablo Bermejo (Madrid, 41 years old) lovingly rocks Teodoro in his arms. He explains that his main interest is the biology of animal and human development: investigating how a single cell – the egg fertilized by the sperm – multiplies with impeccable choreography until it becomes a creature with billions of cells. In humans, half of the fertilized eggs The embryo ends up being lost in a spontaneous abortion, often before the woman even knows she is pregnant, according to data from the National Institutes of Health in the United States. “The mouse is a very bad model for studying this, it has nothing to do with it,” says the Spanish scientist.
Bermejo recalls that in 2016 he requested authorization from the National Biosecurity Commission to generate genetically modified rabbits, goats and sheep. “They said to me: What do you want to do?” he recalls, laughing. The veterinarian had spent time in the laboratory of British biologist Keith Campbell, one of the parents of Dolly the sheep, the first mammal cloned from an adult cell of another animal. Campbell he hanged himself with a belt on October 5, 2012, three days before it was announced that he had not won the Nobel Prize in Medicine. In August 2013, Bermejo was working at the United States Department of Agriculture in Beltsville when his superior sent him a study about genetically modified mice using a cheap and simple new technique: CRISPR. “This is too good to be true,” his boss warned him.
The Spaniard immediately tried that tool for edit DNA from a mouse and it worked on the first try. What previously took a month or was impossible could now be done in a few hours. Upon his return to Spain, he decided to ask for permission to apply CRISPR to farm animals. In May 2017, the first 12 rabbits were born. crisperized. Bermejo’s team inactivated one of its genes, linked to the protein ZP4, one of the four that form the shell that surrounds the embryo of mammals before implantation in the uterus. CRISPR, a kind of molecular scissors, is ideal for cutting DNA at a specific point and silencing the desired gene, which allows us to know its function. Animals with an inactivated gene are called knockout (KO, as in boxing). Bermejo’s rabbits demonstrated that the ZP4 protein is essential and its disappearance causes infertility.
The cock-a-doodle-doo sounds of a rooster, belonging to a neighbouring project to recover native breeds. The stately building of the defunct Francoist institute is today the Animal Reproduction Department of the National Institute of Agricultural and Food Research and Technology (INIA-CSIC). The façade of the experimental farm is decorated with enormous photographs of bungalows on paradisiacal beaches, bucolic images that contrast with the smell of animal excrement. In one room there are 20 white rabbits. knockouts. One of the inactivated genes is the one that produces the TMEM95 protein, whose elimination causes male infertility. Bermejo’s team already revealed in 2020 in mice crisperized that TMEM95 was the third known sperm protein that is essential for fertilization of mammals.
The veterinarian Priscilla Ramos (Burgos, 37 years old) coordinates the research group with Bermejo. He says that, when Teodoro was born, they actually preferred a female. The scientists used CRISPR to deactivate a gene in the embryo linked to the eggs, presumably essential for fertilization. But Teodoro does not have eggs to be able to study the effect of genetic modification. The goal now is to generate a female lamb. crisperizedwhich may be called Zara, like the fashion chain.
In 2022, Ramos, Bermejo and their colleagues created a chemical cocktail—with hormones, proteins, vitamins, lipids—in which they managed to cultivate, for the first time in the world, a fertilized sheep egg. for 14 days on a lab plate. Researchers were on the verge of witnessing the enigmatic gastrulation, the week-long process in which the little ball of cells transforms into the first draft of the creature. The British embryologist Lewis Wolpert (1929-2021) summed it up with a proverbial phrase in his discipline: “The most important moment of your life is not your birth, nor your marriage, nor your death, but gastrulation.” Hidden in the uterus, it is the most unknown phase of human embryonic development.
“The mouse is a very comfortable species to work with in the laboratory, because it requires less space and less investment, but gastrulation in sheep is much more similar to that of humans,” says Ramos. The gestation period of a mouse lasts about 20 days. It is possible to have a specimen knockout in just one month. In sheep, with a pregnancy period of 150 days, it is much more cumbersome. According to Pablo Bermejo, the Madrid facility is the only one that produces farm animals crisperized in Spain, except for two laboratories at the University of Murcia that produce modified pigs genetically. “We have even tried to do it in trout, but it didn’t work out,” the veterinarian admits.
The word CRISPR was invented by the Spanish microbiologist Francis Mojica. In the summer of 1992, he discovered some strange repetitions in the DNA of a microorganism captured in Santa Pola (Alicante). He ended up using them baptizing CRISPRwhich stands for “clustered regularly interspaced short palindromic repeats,” although her partner warned her that CRISPR sounded like a dog’s name. It was a defensive system for microbes, which embedded the genetic material of their enemy viruses in their own DNA, so as not to forget them. When these aggressors returned, the microorganisms recognized them thanks to the CRISPR system and sent molecular scissors to destroy them. In 2012, French biochemist Emmanuelle Charpentier and American chemist Jennifer Doudna They realized that these microbial scissors could be used to rewrite DNA. They won the 2020 Nobel Prize in Chemistry.
A handful of scientists around the world are trying another way to observe the mysterious gastrulation. Pablo Bermejo mentions the work of biologist Magdalena Zernicka-Goetza researcher at Cambridge University who last year announced the creation of “human embryoids”: cells derived from surplus embryos from a fertility clinic, reprogrammed to generate three-dimensional structures that attempt to imitate the development of a real embryo. “They are trying to reconstruct the human embryo with the map of a mouse,” says Bermejo, who also manipulates goat and cow embryos, without ever transferring them to a mother. “We have a hard time fighting against the disease.” establishment of the mouse, but we continue, against the current,” adds the veterinarian, while Teodoro jumps on the straw.
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