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July 23, 2015

A Tap of Radiation Enhances Gene Editing of Human Stem Cells

  • Human pluripotent stem cells exposed to low-dose irradiation—too low to cause harm—more readily accept deliberate, targeted genetic interventions. Prodding stem cells with low-dose irradiation could help scientists accelerate the production of disease models. It could also facilitate cell therapy, the correction of genetic defects in patient-derived cells.

    Low-dose irradiation’s introduction to gene editing has been arranged by researchers in the Cedars-Sinai Board of Governors Regenerative Medicine Institute. These researchers, who report that they have developed a low-dose irradiation (LDI) technique, say it is possible to increase desired gene modifications by an order of magnitude.

    The researchers described their LDI technique in an article that appeared July 16 in Stem Cells Translational Medicine. The article—“Low-Dose Irradiation Enhances Gene Targeting in Human Pluripotent Stem Cells”—indicates that their LDI technique works by facilitating homologous recombination (HR), the inefficiency of which has complicated the development of isogenic control or reporter lines.

    “[Limited LDI] using either γ-ray or x-ray exposure (0.4 Gy) significantly enhanced HR frequency, possibly through induction of DNA repair/recombination machinery including ataxia-telangiectasia mutated, histone H2A.X and RAD51 proteins,” wrote the authors. “LDI could also increase HR efficiency by more than 30-fold when combined with the targeting tools zinc finger nucleases [ZFNs], transcription activator-like effector nucleases [TALENs], and clustered regularly interspaced short palindromic repeats [CRISPR].”

    One of article’s co-senior authors, Clive Svendsen, Ph.D., asserted that low-dose irradiation “allows for far more efficient gene editing of stem cells and will increase the speed of new discoveries.”

    The researchers used whole-exome sequencing to confirm that LDI did not induce gross genomic alterations or reduce overall cellular viability. According to a press announcement issued by Cedars-Sinai, the LDI technique could be used to:

    • create disease mutations in normal cells, thus modeling human disease.
    • correct disease causing mutations and, theoretically, cure the disease in the petri dish.
    • insert reporter genes that glow when a stem cell turns into a specific cell of the body.

    "The combination of low-dose irradiation and correct gene copy will accelerate our ability to model human disease using stem cells from patients with many different disorders," said co-senior author Vaithilingaraja Arumugaswami, Ph.D.

    Over the past few years, the field of creating human diseases in the dish using stem cells has expanded rapidly. This work allows scientists to test novel drugs on human cells that carry disease-causing genes.

    "Radiation, which is normally considered harmful, has proven beneficial in gene editing," added Dr. Svendsen. This new technique will help us establish far more accurate models and accelerate the discovery process."

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