Thursday, January 26, 2023

Spanish scientists revive proteins from millions of years ago and use them to cure albinism in human cells

Microbiologist Francis Mojica in Salinas de Santa Pola (Alicante) in 2017.Raul Bellinchon.

For years, scientists around the world have been searching for microbes in the ice of Antarctica, in the deepest trenches of the oceans and in some of the most hostile volcanic environments on the planet. Their goal is to discover new proteins that can be used to improve current gene editing techniques. This could open the door to a new era of science and medicine in which many diseases can be treated by editing the genome of patients with surprising ease. Today a study led by Spanish scientists is published that is unique in that it discovered these new molecules not in space, but in time: they reconstructed proteins from extinct organisms that lived billions of years ago. Is done.

Researchers have focused on recreating Cas9 enzymes, molecules that act like scissors capable of cutting the DNA of any living organism at a specific point and that are the basis of the CRISPR system of gene editing. Since it was devised in 2012, the technique has revolutionized biomedical research, as it makes it possible to rewrite the instruction book of any organism, and it is now beginning its first application in the treatment of certain diseases in humans. doing. But this editing system is not perfect. This can introduce potentially dangerous errors into the genome. Therefore, there is a need to look for new genetic editing tools.

CRISPR is the immune system of many bacteria and archaea. This allows them to embed virus genetic sequences into their genomes to preserve their robotic portrait. If the virus reappears, CRISPR identifies it and Cas9 truncates its genome to eliminate it. One of the biggest questions in this field is how this bacterial immune system, which is much older than humans, originated.

In search of answers, a team made up of some of Spain’s leading gene editing experts used a technique that reconstructs the genomes of extinct organisms. The technique is known as ancestral sequence reconstruction. It uses powerful computers to compare the complete genomes of things alive today – each made up of billions of letters of DNA – and estimate what the genome of their common ancestor would have looked like. In this way, researchers have taken an amazing journey through time to recover the Cas protein present in an extinct microbe. The oldest they have ever been found dates back 2,600 million years. They have also made intermediate stops to conserve extinct proteins from microorganisms that lived 1,000 million, 200 million, 137 million and 37 million years ago.

Researchers have created new CRISPR systems using these ancient proteins and injected them into human cells. results, published in nature microbiologyshow that despite being so primitive, all proteins are capable of editing the genome.

Researchers have seen something akin to rapid growth in the lab. The oldest protein of all can only cut one strand of DNA, perhaps the simplest and most primitive—human DNA is made up of a double strand. But the more recent Cas molecules can already cut human DNA with increasing effectiveness and in fact they have been able to fix two genes, Tire why OCA2which causes albinism.

In the early 90s of the last century, the biologist Francis Mojica gave his name to CRISPR as part of his study of microbes living in the hostile environment of the salt flats of Santa Pola (Alicante), for which he was in a job . Nobel’s Pool. The researchers also analyzed other sequences called PAMs that are fundamental, as they allow the microbe to distinguish between the virus’s genome and its own. Without PAMs, a bacterium can kill itself. The study shows that the oldest Cas is cleaved without the need for PAM. Mojica, a co-author of the current work, highlights its importance for understanding the origin and evolution of CRISPR. “Thanks to this reconstruction, we see how the immune system of microbes became less harmful to their carriers and increasingly specific to each virus,” he highlighted. Furthermore, “this work is important because it opens up a huge toolbox for building better CRISPR systems,” he says.

Raul Pérez-Jiménez, a researcher at the NanoGuine Basque Center for Cooperative Research in Nanoscience and co-author of the study, details the potential of the study. “These are the oldest Cas proteins ever obtained. We think they are like diamonds in the rough. Now we are going to study how we can make them as efficient as the existing ones or even better”, He explains.

The fact that the early proteins were more generalist may have been an advantage, allowing them to do things that current CRISPRs are not capable of, such as cutting double and single stranded DNA and RNA sequences at the same time. “They’re like Swiss Army knives. They have scissors, corkscrews, needles, screwdrivers. They’re probably not the best tools in their class, but they have them all”, details Pérez-Jiménez.

The researchers and their partner Borja Alonso Lerma have patented these new molecules, which have been purchased by Integra Therapeutics, a company co-founded by Marc Gail, a scientist at Pompeu Fabra University in Barcelona who is also a co-author of the study. . , and who is looking for the new editing formula, genetics, to cure various diseases. The company’s Scientific Advisory Board is headed by the charismatic George Church, one of the world’s leading experts in this field.

Miguel Angel Moreno Pelayo, head of genetics at Madrid’s Ramon y Cajal Hospital and co-author of the work, highlighted that reconstructing ancient proteins opens up the possibility of designing new forms of synthetic CRISPR “that do not exist in nature”. Is.” In other projects, his team develops these types of molecules to try to correct genetic defects in patients with amyotrophic lateral sclerosis. “We are facing a new paradigm”, said the scientist.

One of the people responsible for the study, Luis Montoliu, a researcher at the National Center for Biotechnology in Madrid, highlights another advantage of primitive Cas proteins. The gene editing potential of the CRISPR system was discovered in bacteria of the species S. pyogenes, These microbes can cause infections, so many people have antibodies that can trigger an immune response against the CRISPR extracted from them. Primitive Cas, on the other hand, are very different from any extant variants, so they are not detected by the immune system, a huge advantage for avoiding rejection in future medical applications, argues Montoliu.

The researcher proposes a final reflection on the results of the study. Why haven’t eukaryotes, the large group of multicellular organisms to which we humans belong, developed a CRISPR-based immune system? “Because it is dangerous,” argue the scientist. “The most primitive CRISPR systems already allowed DNA to be cut, but they were very unselective, which might have killed the very organism they were trying to protect. In the world of bacteria, the individual is not important. What matters is the population, and this system allowed them to evolve and perfect an immune system, even at the cost of killing many people along the way,” he concluded.

Miguel Angel Moreno Mateos, an expert in gene editing at the Andalusian Center for Developmental Biology, celebrated the new study. “Especially attractive is the revival of [proteínas] analysis of ancient Cas9 and their activity billions of years later”, he highlighted. “These regenerated Cas9s offer new possibilities with great potential in biotechnology, although further studies and analysis must be done for this to become a reality,” he said further.

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Nation World News Desk
Nation World News Desk
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