A pioneering team from the Perelman School of Medicine at the University of Pennsylvania has made a groundbreaking leap forward in the development of human artificial chromosomes (HACs), a technological feat that could revolutionize advanced gene therapies and numerous laboratory applications.
Their research, recently detailed in the journal Science, presents an innovative method that overcomes one of the most challenging obstacles in the field: the unpredictable assembly of DNA constructs used in creating HACs.
Historically, the construction of HACs was fraught with complexity. Traditional methods often resulted in the DNA constructs unexpectedly linking together in lengthy chains, leading to HACs with erratic structures and functions.
This unpredictability has been a significant barrier to the reliable use and therapeutic application of HACs, particularly in combating diseases like cancer.
The breakthrough by the Penn Medicine researchers involves crafting HACs from singular, elongated pieces of designer DNA. This approach not only simplifies the creation process but also ensures the HACs can be produced more rapidly and accurately.
Such precision is crucial for accelerating DNA research and, potentially, for developing more sophisticated cell therapies.
Dr. Ben Black, the study’s lead and a professor at Penn, emphasized the transformative nature of their work, stating that their redesigned HACs could greatly benefit biotechnological applications, especially in scenarios requiring large-scale genetic engineering of cells.
Unlike their predecessors, these HACs coexist with a cell’s natural chromosomes without necessitating any alterations to them, a feature that promises safer and more efficient genetic modifications.
Human chromosomes, with their intricate structures and complex centromeres (the central region where the arms of chromosomes meet), pose a considerable challenge for artificial replication.
While smaller, simpler chromosomes of organisms like bacteria and yeast have been successfully engineered in the past, human equivalents have remained elusive due to these complexities.
The new technique introduced by the team uses larger DNA constructs and an innovative yeast-cell-based delivery system, allowing for the formation of HACs from single copies of these constructs.
This strategy not only avoids the complications associated with DNA multimerization but also yields HACs that can replicate themselves during cell division, a critical aspect of their potential therapeutic use.
Artificial chromosomes hold significant promise for gene therapy, offering a more reliable and durable platform for gene expression compared to current virus-based methods, which can provoke immune responses and cause unintended integrations into the genome.
They could enable the expression of large gene groups necessary for producing complex proteins, providing unparalleled opportunities for treating a wide array of diseases.
Moreover, the implications of this research extend beyond human health, with potential applications in agriculture, such as developing pest-resistant, high-yielding crops.
The collaborative effort, involving contributions from the J. Craig Venter Institute, the University of Edinburgh, and the Technical University Darmstadt, signifies a major step forward in the utilization of artificial chromosomes for a broad spectrum of applications in science and medicine.
The research findings can be found in Science.
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