DNA editing, not if but when

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by Gregory Tranah, PhD

In August 2017, researchers at Oregon Health Sciences University published study results showing that they had successfully edited the DNA of viable human embryos (http://dx.doi.org/10.1038/nature23305). The goal of the project was to repair a pathogenic DNA mutation in the MYBPC3 gene which leads to hypertrophic cardiomyopathy (thickening of the heart muscle) which is the leading cause of sudden death in young athletes. However, within one month a team of prominent stem-cell scientists and geneticists questioned whether the mutation was actually fixed citing that no plausible biological mechanism explains the results and the original finding was based on poor genetic techniques.

Whether or not the work done by researchers at Oregon Health Sciences University was successful in fixing the disease-causing mutation, the day when we will be able to edit germline DNA is quickly approaching. While the goal of the research was to correct a single mutation that causes a devastating inherited disease, some critics are concerned that such experiments will open the floodgates to a brave new world of “designer babies” engineered with numerous genetic enhancements.

Given that DNA editing will become a reality, we need to not only discuss when it will be appropriate to use this technology but also what limits and risks are likely to emerge as we move down this path.

So, when do you think it be appropriate to use genetic engineering?

Would you use gene editing to fix known mutations that cause deadly, single gene disorders (e.g. Cystic Fibrosis)? Many people may not take issue with this corrective action since carriers definitely acquire the disease and we know the specific mutations responsible for the disease in order to target DNA editing.

Would you use gene editing to fix mutations in genes that greatly increase familial disorders (e.g. PINK, PARKIN, LRRK2 gene mutations in familial Parkinson’s Disease)? We know the specific mutations that increase risk of developing disease for these rare forms of familial disease. However, not every carrier of one of these mutations develops disease so it is not clear what other factors are involved in these devastating diseases.

Would you use gene editing to fix mutations in genes that increase risk of chronic or age-related disease (e.g. Alzheimer’s)? In general, genetic variation is responsible for a only a portion of disease burden for most chronic conditions (~10-50%), but there are environmental effects that cannot be accounted for in genetic  engineering. Also, individual mutations account for a very small risk related to disease (<1%), so how much DNA would you be willing to change in order to impact a very small risk of developing disease? Especially when there may be unintended consequences of the DNA editing.

Would you change DNA to impact other traits (height, eye, color, etc.)? As with chronic disease, there are many DNA mutations that contribute very small effects to a trait. Indeed, there are >700 known DNA variants that contribute a tiny amount to height and there are a huge amount of genetic and environmental factors that are still being identified. Would you be willing to risk unintended consequences related to these mutations (e.g. height is associated with higher cancer risk, green eyes are associated with increased melanoma risk, etc.).

What about the three parent babies that are engineered when mothers carry very deleterious mutations in their mitochondrial DNA? This procedure creates babies with a paternal genome, the mother’s nuclear genome, and a donor’s mitochondrial genome. This procedure produces genetic combinations that would never occur naturally. Three parent babies are approved in the UK but not in the US (yet). Before rejecting this procedure in the US, the FDA had proposed that only male offspring could be produced using this procedure as males do not pass on their mitochondrial DNA, thus these three genome combinations will never be intercalated into the population.

What do you think?

It’s not a matter of if but when… when will it happen and when will it be used.