Genomic Medicine Institute - Center for Personalized Genetic Healthcare


Researchers Experiment with CRISPR Technology to Edit Genomes

By Charis Eng, MD, PhD

CRISPR technology used to correct gene mutation related to inherited heart disease in preimplantation embryos

In August, researchers from The Center for Embryonic Cell and Gene Therapy at Oregon Health & Science University published a study that made headlines. They used CRISPR/CAS9 in human preimplantation embryos to correct a gene mutation related to inherited cardiac disease. Researchers targeted a mutation in MYBPC3 - a gene that, when mutated (altered), causes hypertrophic cardiomyopathy (HCM). HCM is a heart disease affecting 1 in 500 adults, and is a leading cause of sudden death in young athletes.

Gene mutations are like typos

There are approximately 30,000 genes in a human cell, like 30,000 encyclopedias with DNA sentences that must read correctly for the body to function well. Some genes are large, like a big encyclopedia with many volumes and others small, a one-volume encyclopedia. A gene mutation is a severe typographical error in one of the body’s encyclopedias that predisposes individuals to an inherited disease. The power of genetics research has gifted physicians with the ability to make precise gene-informed diagnoses and provide gene-guided medical management, such as increased clinical screening and preventative measures. But won’t it be nice to be able to edit out the gene mutation?

A new technology, CRISPR/CAS9, has been used in research for many years. I use it in my lab. The reason why it hasn’t been used in human genomes yet is because it can introduce even more, unintended typographical errors (we call this off-targeting), instead of correcting the gene mutation (the original typographical error).

This paper in Nature is very exciting for two important reasons. First, the authors show a significant reduction in the off-target creation of typographical errors. Second, they were only trying to correct the MYBPC3 mutation, which leads to a severe, life-threatening disease. It is important that I emphasize both these points.

What is CRISPR?

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is a gene editing system - like an edit/replace feature for a misspelled word in a document. Through a guide RNA sequence, CRISPR can be programmed to find a specific problematic portion of genetic code. Then, using a CAS nuclease enzyme, in this case CAS9, CRISPR technology edits the error in the DNA sequence, and is capable of pasting other (correct) bits of DNA sequence at the site.

Why is CRISPR so controversial?

First, there is the ethical discussion of gene editing. This isn’t about making designer babies. The National Academies of Science, Engineering and Medicine have recently released their decision that human genome editing should be used only to correct for life-threatening diseases, and under tight regulatory control, as I believe this study has done.

Aside from discussions related to the ethics involved in gene editing, scientists are also concerned about the off-targeting effects of CRISPR/CAS9. I think this study shows promise, but much more needs to be done from a research point of view.

How long might it be before we’re using CRISPR genome editing?

Usually once there’s a pilot study such as the one published in Nature, clinical trials could ensue. However, in the United States, clinical trials for gene editing are not allowed. I suspect that these cutting edge clinical trials will not be done in the United States. Careful clinical trials will have to be done and replicated that show that it’s safe and truly corrects the typographical error. We hope that this is in the next 5-10 years, but that’s only a guess.

Think back to the original in vitro fertilization (IVF). I was only a kid, and the science was very exciting. There was this huge hoopla when the first IVF was done at the University of Cambridge in England. Now, we perform IVFs every day. As more and more research is published, and there’s more assurance that genome editing is safe, and we only do it for life-threatening diseases, I suspect that gene editing, whether by CRISPR/CAS9 or other technologies, might come to fruition.

Now, what happens if we find that there are awful off-targeting side effects that we haven’t even thought about? Then, hopefully a new technology would be developed. This is where innovation comes in.

*Note: This article is adapted from an interview I gave on WVIZ’s Ideastream. To watch the video, click here.

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