Other Speedbumps Ahead?

Before CRISPR-Cas9 can become a routine part of the clinical toolkit, researchers must address several other potential challenges.

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One concern is the fact that genes are frequently pleiotropic, affecting multiple molecular pathways. Just because a gene promotes tumor growth does not imply that it lacks other, beneficial effects.

Take the apoptosis or cell-suicide-mediating tumor protein 53 (TP53)’s role in elephants’ low cancer mortality rates, for example.2 Elephants harbor at least 20 copies of TP53.

According to Dr Ewald, “these organisms amplify an apoptosis barrier. A key molecule for regulating apoptosis is p53. As you look across species, you see additional barriers in species that would otherwise be very vulnerable to cancer, because they’re big.

“If elephants have solved that problem with more copies of TP53, then the temptation would be to just insert more p53 into humans.

But the problem is that if you’re putting a gene into an organism that has undergone evolutionary selection pressures that have adjusted all of a gene’s pleiotropic effects, then you affect those, too,” Ewald cautioned. “p53 influences a tremendous number of molecules, and, in turn, they influence other molecules. Natural selection acts on the whole organism, the whole network.”

Those complex pleiotropic effects can lead to very different functions for the same genes among different species.

Tumor necrosis factor (TNF) genes are so-named because in mice, they “wiped out tumors,” Dr Ewald noted. “But in humans, it actually promoted tumor development. We know now that TNF interacts with a tremendous number of molecules, so it’s not surprising that, depending on the environment or conditions in neighboring cells, it could have different effects.”

It can be “mind-boggling” to consider the number of downstream interactions occurring when concentrations of even a single cytokine are altered. “How do you ever use that therapeutically? Well, that’s probably going to be messy. It’s normally not so messy because messy solutions are ‘weeded out’ by natural selection.”