Two papers published today in Nature Medicine are raising a new potential red flag with CRISPR-Cas9 gene editing: Human cells that are successfully edited in the lab may have a genetic malfunction known to drive many types of cancer.
That genetic defect occurs in the gene is p53, nicknamed the “guardian of the genome” for its ability to help keep cell division in check, repair damaged DNA, and order a cell to commit suicide when something goes wrong. When p53 is not working, tumors can grow. Researchers reported in the Nature Medicine papers that dysfunctional p53 activity might be what allows CRISPR-Cas9 gene editing to work in human cells.
Stocks of the three publicly traded U.S. companies developing CRISPR-based therapeutics, Editas Medicine (NASDAQ: EDIT), Intellia Therapeutics (NASDAQ: NTLA), and CRISPR Therapeutics (NASDAQ: CRSP) were down today 8 to 14 percent after the papers—one from a team at the Karolinska Institute in Sweden and the other from the Novartis Institutes for Biomedical Research in Cambridge, MA—were published. None of the three CRISPR companies have begun human testing as of yet. (The FDA suspended the plans for what could’ve been the first human trial of a CRISPR therapy in the U.S., from CRISPR Therapeutics and Vertex Pharmaceuticals; the companies didn’t cite safety problems, however.)
To be clear, the edited cells that the researchers were studying in the lab didn’t suddenly turn into tumors.
The group in Sweden used CRISPR-Cas9 gene editing on a type of human retinal cell that has been studied as a possible cell therapy for certain forms of blindness. The Karolinska team found that the DNA cuts made by the CRISPR-Cas9 system led p53 to do what it’s supposed to do: kick off a DNA-repair process, and ultimately cause the cells to stop growing. When the scientists blocked p53, they were able to edit a greater proportion of cells. That may sound like good news for CRISPR drug developers, but inhibiting p53 is like playing with fire because it opens the door to possible cancer growth.
The Novartis team studied human pluripotent stem cells, which are known to be tougher to edit with CRISPR than other cell types. They found that the CRISPR-made DNA cuts killed most of the cells because the p53 was doing its job. The scientists warn that successfully CRISPR-edited cells that survive the process could be more likely to harbor p53 mutations and turn cancerous.
This p53 risk doesn’t apply to all uses of CRISPR that are now moving towards clinical testing. One of the authors of the Karolinska paper, Bernhard Schmierer of the Karolinska, told Stat that the results from the two papers are preliminary: “It is unclear if the findings translate into cells actually used in current clinical studies.”
Still, the authors of both papers say their findings are a warning to developers of CRISPR-based therapies: Edited cells should be monitored for any p53 mutations. As the Novartis team wrote in its paper, for any therapies that involve editing patient stem cells: “…it will be critical to ensure that patient cells have a functional P53 before and after [genome] engineering.”
This isn’t the first time that researchers have sounded alarm bells about possible problems CRISPR gene-editing may inadvertently cause in humans. A paper in 2017 claimed that CRISPR could make a lot of off-target edits, but the authors later retracted it. Another paper this year said that the human immune system could attack Cas9, although researchers say there are workarounds.