Is the CRISPR Craze a Rerun?

Some years ago there was a basic science discovery that took the biomedical field by storm. Scientists working in a model organism had found a way to selectively target nucleic acids in the cell, shutting down gene expression. There was a ton of hype over the next several years, with everyone imagining the therapies that would start to help patients in no time.

You might think that I am talking about CRISPR; everyone else is, after all. But I am talking about RNAi, which was once touted as the discovery that would revolutionize medicine forever. I was talking to a colleague who is a bigwig in the CRISPR field who was speculating about the future of his field when he said something that shocked me at first. He suggested that CRISPR will not be the revolutionary clinical discovery that some people think it will turn out to be. When I pressed him, he compared it the hype behind RNAi a decade ago. Given this perspective, a couple of questions started to float around in my head. How similar was the hype behind RNAi to that of CRISPR/Cas9 today? Could CRISPR lead to the same letdown?

I did not know much about the RNAi craze–I know RNAi as a handy lab technique, but I never thought of it as a viable clinical treatment–so I went back and did some Googles. RNAi, which stands for “RNA interference,” is a set of cellular systems that cut up RNA and use the pieces to target and attack matching RNA transcripts in the cell. This turns down the expression of certain genes, which can be an effective way of doing genetic experiments in the lab.

It did not take much imagination to dream of how RNAi could be useful in treating human disease. Since plenty of diseases are due to the expression of disease-causing genes, doctors could treat the disease by giving the patient a drug to mobilize the RNAi system against the disease gene.

But in practice, RNAi ended up being difficult to use in patients. Hopes for RNAi therapy peaked during the mid 2000s, and started to ebb during the next few years after human trials showed no real benefit to patients or led to unintended immune responses.

Some people were afraid that RNAi would never live up to its promise. Biotechnology companies shuttered their RNAi research divisions. Human trials slowed down. Luckily, things did bounce back. There are still companies today working on RNAi therapies. It would seem that RNAi was over-hyped, it nearly crashed, then it became what it was always going to be: a therapy with some promise, but no miracle.

Today, CRISPR is just as hyped as RNAi was back then…if not more. CRISPR genome editing is popular science. In many ways, the lay public believes that this will be the century of biology: we will crack the mysteries of aging, we will edit human embryos to eliminate genetic disorders, we will cure all of the diseases. CRISPR genome editing is at the center of these hopes. But there are lessons to learn from the original breakthrough to end all breakthroughs. RNAi was not a complete failure, but we were certainly naive about its potential.

Part of what we got wrong was how unrealistic we were about the limitations of RNAi technology. Living cells have strong negative reactions to double-stranded RNA, which is a necessary step in the RNAi pathway. Delivery systems would be hard to engineer, just like the problems that still plague gene therapy. Finally, there is something that RNAi and CRISPR have in common: off-target effects.

Both RNAi and CRISPR depend on nucleic acids lining up and binding to each other in a pairwise manner before they can have their effect. Since the RNA sequences that bind to targets in RNAi and CRISPR are short and there is quite a bit of nucleic acid sequence in the cell, there is a possibility that you will get your molecule pairing up with an unintended target. It is like taking a short sentence fragment at random from a book and then searching the book for that fragment. You can find the target that you are looking for, but you might also find other perfect or near perfect matches elsewhere in the book, especially when you are searching through a large, complex book.

When these off-target effects happen with RNAi, you could shut down the expression of another gene. If that other gene is important, you might risk harming the cell. The same thing can happen with CRISPR. In fact, CRISPR has the potential to have more dire off-target effects:  CRISPR involves changing the DNA archive, rather than the RNA copy, which can lead to irrevocable changes to the cell.

Luckily, it does seem like CRISPR researchers have taken this to heart. Research into CRISPR’s off-target potential is an active field. I even blogged about a system that might be able to fine-tune the activity of CRISPR/Cas9 with the goal of reducing off-target effects in CRISPR therapy.

To be fair, CRISPR is at least a decade away from the clinic. But there are reasons to be concerned. Scientists have edited human embryos, and ethicists are scrambling to come up with rules to inform how we use this technology. If we learned anything from the RNAi experience, we should carry it over to CRISPR/Cas9. These systems seem to break out onto the scene with a ton of potential and bold claims. Eventually, we might be disappointed. There might be CRISPR trials somewhere down the road that will have to stop, with patients who thought they might be helped instead left wondering what all the hype was about. But if we have learned anything, it is that these systems will change our world. We will end up better off because of CRISPR. We just have to be willing to take the time to figure it out first.

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