Embryonic stem cells could help treat all kinds of disorders, and editing the genomes of these stem cells could make the treatments far more potent. But there might be a catch.
A team at Novartis has found that genome editing kills most human embryonic stem cells – and that the ones that do survive are likely to have mutations in a key anti-cancer gene. Cells with such mutations are in theory far more likely to turn cancerous if implanted in the body.
“It’s an important practical finding,” says Florian Merkle of the Wellcome-MRC Cambridge Stem Cell Institute in the UK, who was not involved in the work. “This is something we need to be aware of and test for.”
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Embryonic stem cells (ESCs) are derived from embryos or created by reprogramming adult cells. They can turn into any cell type in the body, so they have enormous potential for treating a huge range of diseases, from macular degeneration to Parkinson’s to diabetes.
Earlier this year, for instance, it was reported that the vision of two people with severe sight loss had greatly improved after retinal cells grown from ESCs were implanted in their eyes.
Genome editing can make such therapies even more powerful. For instance, if a person has a disease caused by a specific mutation, ESCs could be derived from cells taken from their body, the mutation corrected and healthy tissues re-implanted in the body.
Suspect cell death
But when Ajamete Kaykas’s team at the Novartis Institutes for Biomedical Research in Boston tried to use the CRISPR gene-editing technique to edit ESCs, most of the cells died. Further studies revealed that the deaths were due to a protein called P53.
P53’s normal role is to prevent cancer by triggering cell suicide when it detects dangerous mutations. The standard form of gene editing involves inducing mutations by cutting DNA at a specific point, which appears to make p53 kick into action.
What’s worrying is that the cells that did survive were far more likely to have mutations in p53. If gene-edited ESCs with a disabled p53 were turned into rapidly dividing cells like skin cells and implanted in the body, they could acquire even more mutations and turn cancerous. The risk would be much lower if ESCs were turned into non-dividing cells such as neurons.
Other researchers are surprised by the results. “I’m inclined to believe this study but I still have some questions,” says Merkle. In particular, DNA breaks occur naturally in cells all the time, so it’s not clear why those made by CRISPR should produce such a strong cell-suicide response in ESCs.
Another question is whether it happens in other cell types. “Different cells have a different repertoire of DNA repair enzymes,” says Ben Davies of Oxford University. “So it’s hard to predict whether this phenomenon will create the same kind of cell death response in other cell lines.”
New forms
The good news is that we may already have solutions. Biologists have developed advanced forms of CRISPR gene-editing, called nickases and base editors, that don’t completely sever DNA strands. “These would not trigger the problem,” says Robin Lovell-Badge of the Francis Crick Institute in the UK.
It should also be standard practice to check cells grown in labs for p53 mutations, says Merkle. His team showed last year that . This could skew research done with the cells, which are being used to study and test treatments for all kinds of genetic disorders.
No clinical trials involving gene-edited ESCs have yet begun. But a company called CRISPR Therapeutics plans to treat β-thalassemia and sickle cell disease by editing each individual’s blood stem cells. On 30 May, , for reasons that have not yet been made public.
