The Evolutionary Implications of CRISPR-Cas9 for Clinical Oncology

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CRISPR is receiving attention as a gene-editing tool that may help us treat cancer, but evolutionary theory suggests a much more complex reality.
CRISPR is receiving attention as a gene-editing tool that may help us treat cancer, but evolutionary theory suggests a much more complex reality.

Biologists long assumed that adaptive immunity, in which immune systems learn to recognize and attack specific strains of pathogens, evolved only in animals. But the discovery of clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune systems in prokaryotes—single-celled bacteria and archaea—proved otherwise, handing biologists an unexpected and powerful new tool for genome editing.1

“Long-lived organisms are the ones you really expect to have immunological memory,” said Paul Ewald, PhD, an evolutionary biologist who specializes in the study of infectious disease. Dr Ewald directs the evolutionary medicine program at the University of Louisville in Kentucky.

But CRISPR is just such a system: an adaptive memory system for short-lived prokaryotes. That seems to violate the principal that only longer-lived organisms will evolve adaptive immune systems. “But I think if we look at it from an evolutionary point of view, through fission-division, bacteria are essentially immortal,” Dr Ewald noted. “The lineage is like an immortal organism, so it makes a lot of sense that they keep track of viruses they've encountered.”

CRISPR and enzymes known as “CRISPR-associated proteins” (Cas) work in concert to allow prokaryotes to keep genomic “scrap-books” of DNA sequences from the viruses they encounter, and to employ those molecular memories to fight viral invasions. When viral genes are re-encountered, CRISPR systems produce RNA templates to spot and inactivate them with Cas proteins, which have been likened to molecular scissors.

One such Cas, Cas9, has quickly gained favor among researchers because it is an elegantly simple gene-editing platform, more easily employed than zinc-finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs). Using guide RNAs, CRISPR-Cas9 can target and inactivate any gene in a living cell. That makes a powerful tool for loss-of-function analyses of particular genes' roles in disease.

It might also provide a genomic scalpel for treating some diseases.

“The beauty of this is that you can correct defective alleles,” Dr Ewald said. “If you can work out the technical details, it could be a great approach.”

But that endorsement comes with some important asterisks.

“I think that, in general, this technology will work well if you have a clear genetic cause of a condition, and if you can actually do the intervention ethically,” Dr Ewald said. “Very conceivably, you could make a lot of progress against something like Huntington disease, which is clearly a genetic disease, or sickle-cell.”

But CRISPR-Cas9's promise becomes less certain when it comes to cancers, he cautioned.

“We are realizing that even within a given type of cancer, the changes in genes are very heterogeneous; there are hundreds of mutations,” Dr Ewald explained. Many tumor mutations are incidental “passenger” mutations that do not actually drive tumor growth, and can't be usefully targeted.

For the few cancers that have a clear genetic basis, like retinoblastoma, CRISPR-Cas9 might offer a relatively straight-forward way to correct the responsible driver mutation, Dr Ewald said. “In principle, you should be able to make a lot of progress.”

In reality, however, cancers with clear, strong genetic predispositions are relatively rare.

“There are good reasons for them to be rare, from an evolutionary point of view, because those genes are ‘weeded out' of the genome by natural selection,” Dr Ewald said.

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