A Possible Problem with CRISPR

Viruses use the DNA of their hosts to help themselves reproduce. Bacteria have counter-attacked viruses by grabbing some of the DNA from viruses and using this to identify them and kill them back. That as an oversimplified description of an eons old arms race between viruses and bacteria.

Among the DNA sequences co-opted by bacteria is the famous gene-frag-family known as CRISPR. You’ve heard of it, and you probably know what it does. Briefly, genetic scientists can use the innate power of CRISPR to manipulate other DNA to “repair” or modify in situ DNA sequences in living organisms. Got a genetic disease? No problem. We get the good genetic sequence, and then use the CRISPR based technology to replace all your bad DNA with the good DNA.

Now, of course, that doesn’t really work this way, and CRISPR technology has had fairly limited success so far. But there have been successes, and CRISPR is generally regarded as the Next Great Hope in the future of genetic therapy.

But now there may be a problem. Among the bacteria that use a CRISPER sort of sequence are two that are fairly nasty and common human pathogens. These are Staphylococcus aureus and Streptococcus pyogenes. In fact, the specific CRISPER sequences that genetic scientists use to do the CRISPR thing, come from these specific bacteria.

So, think about this for a moment. If CRISPER is used by bacteria to do any of their dirty work, and the bacteria are common human pathogens, is it possible that some humans have built up an immunity to the CRISPER sequences, perhaps putting them off limits for future CRISPR therapy?

Yes.

From the abstract of a recent paper:

Based on the fact that these two bacterial
species cause infections in the human population at high frequencies, we looked for the presence of pre-existing adaptive immune responses to their respective Cas9 homologs, SaCas9 (S. aureus homolog of Cas9) and SpCas9 (S. pyogenes homolog of Cas9). To determine the presence of anti-Cas9 antibodies, we probed for the two homologs using human serum and were able to detect antibodies against both, with 79% of donors staining against SaCas9 and 65% of donors staining against SpCas9. Upon investigating the presence of antigen-specific T-cells against the two homologs in human peripheral blood, we found anti-SaCas9 T-cells in 46% of donors. Upon isolating, expanding, and conducting antigen re-stimulation experiments on several of these donors’ anti-SaCas9 T-cells, we observed an SaCas9-specific response confirming that these T-cells were antigen-specific. We were unable to detect antigen- specific T-cells against SpCas9, although the sensitivity of the assay precludes us from concluding that such T-cells do not exist. Together, this data demonstrates that there are pre-existing humoral and cell-mediated adaptive immune responses to Cas9 in humans, a factor which must be taken into account as the CRISPR-Cas9 system moves forward into clinical trials.

This could be a problem. Maybe it is time to look for CRISPR sequences in other more obscure bacteria.

This is all new, and the ultimate meaning of it all remains to be seen. Stay tuned!

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