CRISPR has been one of the most influential breakthroughs of the past decade, yet it remains imperfect. While the gene-enhancing software has already demonstrated its potential in supporting individuals with genetic conditions, researchers continue to push boundaries by exploring further advancements.
Researchers’ persistent endeavors have expanded the CRISPR family by integrating even less harmful, more precise, and compact versions of the gene editor. While CRISPR’s discovery in the bacterial realm is remarkable, it barely scratches the surface of its potential applications. Two groundbreaking studies propose a significantly more potent gene editor is on the horizon – if its efficacy can be verified in cellular environments akin to ours.
Scientists report discovering a novel CRISPR-like gene editing system within bacterial “jumping genes,” which is independently replicated by another research team covering the same software and extending its application to a distinct family member.
Horizontal gene transfer occurs frequently within genomes and occasionally between individuals. Scientists have long recognized that certain organisms modify and paste their own DNA, but none have been shown to be programmable like CRISPR. Scientists have identified novel gene editing strategies, referred to as “bridge-enhancing” and “seekRNA”, which enable modification of DNA sequences by cutting, pasting, and flipping any desired genomic region.
Significantly, unlike CRISPR, the system accomplishes these feats without relying on the potentially hazardous and unreliable process of breaking DNA strands and expecting cellular repair mechanisms to restore order. The molecules involved are indeed less numerous and diminutive compared to those found in CRISPR, which likely renders the tool safer and easier to deliver into cells, while also enabling handling of longer sequence lengths?
According to Patrick Hsu, a senior author at Berkeley and core investigator at Arc Institute, “Bridge recombination can universally modify genetic materials by sequence-specific insertion, excision, inversion, and more, effectively enabling a phrase processor for the resident genome following CRISPR.”
CRISPR Coup
Researchers initially discovered CRISPR in microorganisms that were utilizing the technique to defend themselves against viral infections. Cas9 proteins form complexes with guide RNAs to locate and cleave viral DNA sequences. Scientists successfully modified this approach to identify specific DNA sequences, including those found in human genomes, and cleaved the DNA molecules at these precise locations. The cell’s machinery rapidly repairs these breaks by leveraging a readily available segment of DNA.
CRISPR gene editing has been shown to be remarkably effective in various applications. Researchers are currently exploring the therapeutic potential of this compound in a variety of genetic disorders, with recent positive outcomes in clinical trials, including approval as a treatment for both sickle cell disease and beta thalassemia late last year. However it’s not excellent.
As a consequence of the system’s propensity to break DNA, it relies heavily on cellular mechanisms to rectify these disruptions, thereby introducing potential inaccuracies and unpredictability into the process. The software operates seamlessly on specific segments of DNA. While numerous genetic disorders stem from point mutations that alter a single DNA “letter”, the ability to manipulate longer sequences would significantly expand the field’s applications in both synthetic biology and gene therapy.
Researchers have progressively crafted innovative CRISPR-based systems to mitigate these limitations over time. Several programmes exclusively sever a lone DNA strand or, for greater accuracy, Researchers are actively seeking out additional CRISPR-like systems, while others have already identified.
The newly developed project expands the inquiry by incorporating jumping genes into the blend.
An RNA Bridge
Leaps in gene transmission are a fascinating display of genetic innovation. Transposable elements, sequences of DNA, can move between genomic locations by employing enzymes that facilitate their excision and reinsertion. In microorganisms, they can even transfer between people. The horizontal transfer of genes among microorganisms allows one resistant cell to disseminate its genetic adaptations, potentially shielding an entire population from the effects of a drug.
Researchers at the Arc Institute studied a specific jumping gene in bacteria known as IS110 within the context of their examination. When the gene is activated during transfer, it triggers the production of a specific RNA sequence, similar to those used in CRISPR, which facilitates the process. The RNA structure features a dual-loop configuration: one loop directly interacts with the target gene, while its counterpart navigates to bind at the gene’s specific genomic location. The primer functions as a molecular anchor, linking the DNA sequence to the specific site where it is intended to be integrated. Unlike CRISPR, which allows for the insertion of a specific sequence without disrupting the surrounding DNA once discovered.
“Bridging gaps in DNA sequencing, Hsu’s technique seamlessly integrates cuts and pastes DNA molecules in a single step, preserving their integrity.” That’s distinctly different from CRISPR technology, which generates untargeted DNA lesions requiring subsequent DNA repair and has been shown to elicit unintended DNA damage responses.
Significantly, the scientists discovered that individual loops of RNA can be repurposed. Scientists can pinpoint a precise genomic location, dictating the specific sequence that should occupy that spot. The system has the potential to seamlessly integrate lengthy gene sequences as well as multiple genes, enabling precise genetic modifications. As a proof of concept in microbial organisms, the team successfully engineered E. coli IS10 transposase to insert a DNA sequence approximately 5,000 nucleotides long. Furthermore, they successfully sequenced and reversed one additional strand of DNA.
The examination was accompanied by an independent report from a separate team of researchers at the University of Sydney detailing both IS110 and its associated enzyme, IS111, which they claim is equally programmable. The researchers designated these software tools as “seekRNA”.
The instruments . It may be more straightforward to encapsulate these molecules within harmless viruses or lipid nanoparticles, already employed in COVID-19 vaccines, and deliver them directly to cells where they can exert their effects.
The Subsequent Bounce
While the method exhibits significant promise, a crucial caveat must also be acknowledged. To date, researchers have solely proved its efficacy in microbial systems. Despite its versatility, CRISPR has demonstrated remarkable efficacy across a wide range of cells. Subsequently, they aim to refine the approach further and apply it to human cells. That might not be straightforward. The Tokyo University’s Hiroshi Nishimasu.
Although it’s true that the expert’s knowledge is still developing, it’s still relatively early in their professional journey. While scientists were familiar with the existence of CRISPR technology for several years prior, its programmability remained unclear until confirmation. It wasn’t until 2013 that CRISPR was effectively employed within human cells. Despite the relatively short time frame since transitioning from laboratory to clinical setting, the initial CRISPR-based therapies still required several additional years to become a reality.
The groundbreaking research suggests that our understanding of nature’s capabilities in gene editing is still evolving. Within the realm of artificial biology, technology is equally beneficial, as scientists are studying single cells to understand life’s simplest forms and explore ways to reengineer them. If the cutting-edge system were designed specifically for human cells, it may represent a valuable innovation in the development of safer, more potent gene therapies.
Sandro Fernandes Ataide, a leading structural biologist at the University of Sydney, notes that if this discovery proves effective across various cells, it will likely have a profound impact. The breakthrough opens up an entirely new field of gene improvement.
