There is truth to the aphorism that ‘it’s all in the genes.’ They dictate everything, from how fruit flies fight to a newborn’s eye color. And, genetic mutations are at the roots of dozens of ravaging diseases. For years, medical science has sought a means to make repair at the fundamental levels – in a patient’s DNA - by exchanging defective genes for healthy ones. But it’s easier said than done. Gene-splicing technology is available, but the transplanted genes haven’t always worked as planned. The new genes either get shut off by the patient’s host cells, explains Salk postdoctoral researcher Keiichiro Suzuki, “or they are not expressed as expected because they don't occupy the same position in the genome as the natural genes.” That may change soon.

Recently, a team of microbiologists at the Salk Institute for Biological Studies successfully ‘edited’ a diseased gene in a patient. The study, which will be published in the June 3, 2011 issue of Cell Stem Cell demonstrates that the gene-editing approach developed by Salk professor Juan Carlos Izpisúa Belmonte, Ph.D. and his team opens the way for gene editing-based stem cell therapies suitable for clinical applications. The key to the operation, says Dr. Belmonte, lies in one major arena.

When we last spoke with Dr. Belmonte, a professor in the Gene Expression Laboratory at the Salk, he was busy studying the zebra fish (by all accounts an Olympiad in the category of cellular self-regeneration) in an effort to discover a means by which human hearts might one day repair themselves.

"The ability to derive and grow human pluripotent stem cells has raised enormous expectations within the biomedical community due to their transplantational potential in clinical settings," says Belmonte. Pluriopotency indicates a stem cell that can give rise to virtually any cell type. "This,” he says, “when combined with the development of efficient and safe gene editing technologies in human stem cells may greatly help the realization of these expectations."

The Salk team addressed the shortcomings of previously attempted methods by using an induced pluriopotent stem cell model of a rare genetic disorder, Hutchinson-Gilford progeria that was recently established in Dr. Belmonte’s La Jolla laboratory. Hutchinson-Gilford is a premature aging disease. It is caused by a mutation in the gene that encodes lamin A. Lamins are fibrous proteins that provide scaffold-like structures within the cell nucleus and help to organize processes such asRNA and DNA synthesis. Hundreds of different mutations in the lamin A gene have been reported and are associated with a wide range of human degenerative diseases including muscular dystrophy.

The gene-targeting approach developed by Suzuki and his colleagues delivers large mutation-free DNA molecules into cells. Once there, these replacement pieces initiate a process known as homologous recombination. It works something like the find-and-replace command in a word processor.

The good news is that this time, the process worked. "What's more,” says Salk team member and co-first author Guang-Hui Liu, “it allowed us to show that we can correct multiple mutations spanning large genomic regions."

Researchers who also contributed to the gene swap study include co-first author Jing Qu, Fei Yi, Mo Li, Ignacio Sancho-Martinez, Sachin Kumar, Emmanuel Nivet, Jessica Kim, Rupa Devi Soligalla, Ilir Dubova and April Goebl in the Izpisúa Belmonte lab, Nongluk Plongthongkum, Ho-Lim Fung, and Kun Zhang in the Department of Engineering at the University of California, San Diego, as well as Jeanne F. Loring and Louise C. Laurent in the Center of Regenerative Medicine at the Scripps Research Institute.