Could potential associated cancer risks claw into CRISPR’s potential?

The short answer from both previous and new data is that while CRISPR gene editing impacts the P53 pathway, which is involved in cancer along with having many other functions, this news is neither too surprising nor a fatal flaw, but some caution is warranted.

CRISPR is many things including an exciting technology that my own lab uses a lot, but it isn’t and never will be perfect or somehow magical. When this week’s story (e.g. in STAT here with arguably an over-the-top headline “A serious new hurdle for CRISPR: Edited cells might cause cancer, two studies find”) about a cancer connection came up, it required some reading and thinking to really see what all the buzz was about.

Part of the challenge here is that people have been so enamored of gene editing that some folks hyped it a ton. Investors in gene editing-related companies have also pushed things into the over-exuberance zone too. This all of course set this technology up for a fall or multiple falls back toward rationale reality.

The initial gene editing “don’t panic” moment came when first one and then another paper came out indicating that the human body may have, to put it simply, some immunity to the key CRISPR protein component for standard gene editing, the nuclease Cas9. This is a real, sizable issue, but there are possible workarounds and in a way that news brought a needed taste of reality to the gene editing arena. The path ahead is not a smooth, linear one, but that’s OK.

Now two new research papers in Nature Medicine (here and here) are being portrayed as being some big new “bad news” connection between CRISPR and cancer. The first paper is “CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response”, by a Swedish-UK team led by Jussi Taipale. The second paper is, “p53 inhibits CRISPR–Cas9 engineering in human pluripotent stem cells” from a team led by Ajamete Kaykas at Novartis.

What’s the deal with these papers? How worried should we be?

First, it’s not surprising that using a nuclease system for genetic modification would activate P53 (and some data was already out on this last year), which would in turn stimulate apoptosis. After all, Cas9 creates double-strand DNA breaks. Also, it’s not a shocker that the specific cells that do successfully get gene edited might often find a way around P53-induced apoptosis triggered by Cas9.

Yes, in theory that would then make them more susceptible to oncogenic transformation, but it’s not a given. Furthermore, such events might be made much less frequent in fact by chemically inhibiting P53 transiently during gene editing. Such P53 inhibition may improve gene editing attempts for non-clinical research purposes as well.

P53 pathway status should be monitored both for certain in vitro studies and especially for potential clinical applications. For translational studies that should probably have already been on the to-do checklist, but these papers just reinforce the need. Remember that there’s another “reliable” way to relatively frequently generate individual cells in mixed populations having P53 or other cancer-related mutations: just culturing them for long enough in vitro. in other words, I believe that for cell therapies of any kind P53 pathway status and that of other oncogene-related pathways should always be monitored.

Finally, to say that CRISPR-Cas9 gene editing might “cause cancer” seems premature to me so there probably were and are better ways for people to phrase the big-picture meaning of these new papers and others like them that may pop up in the future. However, to be clear safety is crucial so this is an important development and risks of any potential therapy including gene editing-based approaches should be carefully weighed against potential benefits as trials are designed and then progress.

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