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Researchers from the University of Pennsylvania’s Perelman School of Medicine have devised a novel technique for generating human artificial chromosomes (HACs), potentially transforming gene therapy and biotechnology. Published in Science, their study unveils a method adept at producing single-copy HACs, overcoming a longstanding obstacle in the field.

Researchers develop novel ways of delivering HACs

Artificial chromosomes, mimicking natural chromosomes, are crafted in labs to deliver therapeutic genes or study chromosome biology. Prior efforts were hindered by DNA segments linking unpredictably, forming tangled chains with rearranged sequences.

Dr. Ben Black and his team at Penn Medicine developed a novel approach to designing and delivering HACs, which are highly desirable for biotechnology applications. They achieved this by completely revamping the conventional method. Their HACs can coexist with natural chromosomes in cells without requiring alterations to those chromosomes.

To validate their concept, researchers utilized yeast, a common tool in molecular biology. Employing TAR cloning, they constructed a massive 750 kilobase DNA entity within yeast cells, significantly larger than previous HAC constructs. This DNA included elements from human and bacterial sources, along with centromere-seeding sequences.

The team successfully delivered a large payload into human cells by fusing engineered yeast cells with a human cell line, a method previously optimized. This fusion technique surpassed traditional DNA transfer methods in efficiency. The engineered human artificial chromosomes (HACs) formed with significantly higher success rates. Moreover, these designer chromosomes replicated and segregated correctly during cell division, ensuring their long-term stability and functionality.

HACs offer safer alternative to virus-based gene therapy delivery systems

Dr. Black explained that instead of suppressing multimerization, they addressed the issue by increasing the size of the input DNA construct, promoting a naturally stable single-copy form.

This groundbreaking development in the field of genetics, artificial chromosomes (HACs) offer promising implications. They present safer and more efficient alternatives to virus-based gene therapy delivery systems, mitigating risks like immune reactions and harmful viral DNA integration into the host genome. Additionally, HACs can accommodate larger genetic payloads, enabling the expression of extensive gene networks or complex protein structures.