Modifying, and replacing entire human chromosomes while preserving their structure
An international group of researchers from the MRC Laboratory of Molecular Biology and the Wellcome Sanger Institute in Cambridge, led by Gianluca Petris — now Principal Investigator of the Genome Engineering & Biotechnology Unit at the Fondazione Italiana Fegato and lecturer in the Department of Medicine at the University of Udine – has achieved an unprecedented result: transferring, modifying, and replacing entire human chromosomes while keeping their structure intact. The study, published in Science, represents a decisive breakthrough for synthetic and generative biology and for future advanced genetic therapies.
The researchers developed a technology that makes it possible to move entire human chromosomes from one cell to another without damaging their DNA, to modify them in special “factory cells” made from mouse embryonic stem cells, and then to reintroduce them into final human cells. In these factory cells, the telomeres of human chromosomes – structures whose shortening is critical in aging processes and genomic stability – lengthen up to tenfold, then spontaneously return to typical human lengths once the chromosomes are transferred back into the recipient cells. It was also possible to eliminate the original chromosome from human cells and replace it with the engineered one, completing for the first time a full cycle of chromosome transplantation with unprecedented genomic fidelity.
This approach allows scientists to address biological questions that have so far remained beyond the reach of traditional genome-editing tools (such as CRISPR-Cas). The new technology makes it possible to modify and causally analyze the human genome as an integrated system rather than gene by gene. It therefore becomes easier to evaluate the contribution of large regulatory regions, the role of so-called “dark DNA”, and the three-dimensional organization of DNA in the cell. Moreover, it offers a unique model for studying the chromosomal alterations typical of cancer, as well as the mechanisms underlying aging, including the dynamic behavior of telomeres. Looking ahead, this work paves the way for building synthetic chromosomes and genomes, designing cells with entirely new functions, generating cells and tissues with greater immunological compatibility and intrinsic resistance to viruses, and developing a new generation of gene therapies capable of addressing even complex and rare diseases.
The experimental part of the research was conducted entirely in the United Kingdom thanks to the support of the Medical Research Council (MRC), the Wellcome Trust, and a Marie Skłodowska-Curie European Postdoctoral Fellowship awarded to Dr. Petris during his time abroad.
The continuation and expansion of this line of research in Italy is now being carried out by Dr. Petris at the Fondazione Italiana Fegato and the University of Udine, thanks to competitive funding such as the My First AIRC Grant (AIRC) and the PNRR (Next Gen EU) – Young Researchers program.
As Gianluca Petris emphasizes, “this is a result that only a few years ago would have been considered unattainable, and today it opens the door to a new generation of knowledge and technologies destined to have a major scientific, medical, economic, and social impact”.